TW200406371A - Amide linker peroxisome proliferator activated receptor modulators - Google Patents

Amide linker peroxisome proliferator activated receptor modulators Download PDF

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Publication number
TW200406371A
TW200406371A TW092116259A TW92116259A TW200406371A TW 200406371 A TW200406371 A TW 200406371A TW 092116259 A TW092116259 A TW 092116259A TW 92116259 A TW92116259 A TW 92116259A TW 200406371 A TW200406371 A TW 200406371A
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Taiwan
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phenyl
group
ethoxy
alkyl
propionic acid
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TW092116259A
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Chinese (zh)
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Rafael Ferritto Crespo
Jose Alfredo Martin
Maria Dolores Martin-Ortega Finger
Isabel Rojo Garcia
Quanrong Shen
M Warshawsky Alan
Xu Yanping
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Lilly Co Eli
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Publication of TW200406371A publication Critical patent/TW200406371A/en

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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Abstract

The present invention is directed to compounds, compositions, and use of compounds the structural Formula I.

Description

200406371 玖、發明說明： 【發明所屬之4支術領域】 本發明係有關於醯胺連接劑過氧化物酶體增殖劑活化受 體調節劑。 ^ 【先前技術】 過氧化物酶體增殖劑活化受體（PPARs)係調控基因表現 之經配位體活化的轉錄因子之細胞核激素受體超家族成員 。目前已發現不同亞型之PPARs。這些包括，例如PPARoc、 NUC1、ΡΡΑΙΙγ與 PPARS 〇 經顯示PPARjx、PPARy與PPARS受體涉及糖尿病、心血管 疾病、肥胖症、X症候群與諸如發炎性腸疾之腸胃道疾病。 X症候群係包括伴隨高血壓之高胰島素血症、體重增加、高 三甘油脂與高LDL等症狀之合併。 目前對X症候群採取之PPAR激動劑治療與嘧唑啶二酮 (TZDs)或其他胰島素敏感性增強劑（ISEs)之使用有關。TZDs 係一類經顯示可增加胰島素敏感性細胞敏感性的PPARy激 動劑。增加^液中胰島素之敏感性而非胰島素之量，可降 低低血糖時昏迷之可能。然而，TZDs與ISEs與不必要之臨床 效應相關，故需要經改善之臨床情形。因而，目前對新的 具有所需之藥理情形之藥劑存在需求。當與治療糖尿病與/ 或相關臨床病情所需之安全性情形與所需效果相關時，尤 其需要此類具PPAR選擇性或雙重選擇性之激動劑化合物。 【發明内容】 本發明之具體實施例係針對由下列結構式I所代表之化 合物： 85504.doc -6- 200406371 R5. /R6 R1200406371 发明 Description of the invention: [Four surgical fields to which the invention belongs] The present invention relates to an ammonium linker, a peroxisome proliferator, and an activating receptor modulator. ^ [Prior art] Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that regulate gene expression. Different subtypes of PPARs have been found. These include, for example, PPARoc, NUC1, PPAIIII and PPARS. PPARjx, PPARy and PPARS receptors have been shown to be involved in diabetes, cardiovascular disease, obesity, syndrome X and gastrointestinal diseases such as inflammatory bowel disease. Syndrome X includes the combination of hyperinsulinemia with hypertension, weight gain, high triglycerides, and high LDL. The current treatment of PPAR agonists for syndrome X is related to the use of pyrazolidinones (TZDs) or other insulin sensitivity enhancers (ISEs). TZDs are a class of PPARy agonists that have been shown to increase insulin-sensitive cell sensitivity. Increasing the sensitivity of insulin in the fluid instead of the amount of insulin can reduce the possibility of coma during hypoglycemia. However, TZDs and ISEs are associated with unnecessary clinical effects, so improved clinical situations are needed. Therefore, there is currently a need for new agents with the required pharmacological profile. Such PPAR-selective or dual-selective agonist compounds are particularly needed when the safety profile required to treat diabetes and / or related clinical conditions is related to the desired effect. [Summary of the Invention] A specific embodiment of the present invention is directed to a compound represented by the following structural formula I: 85504.doc -6- 200406371 R5. / R6 R1

〇 R2 (a) R1係選自下列各基組成之群：氫、CVC8烷基、C3-C6 環烷基、芳基-CG_4-烷基、雜芳基-CV4-烷基、胺基Ci-C^ 燒基、C3-C6環燒芳基- C〇_2_燒基、芳基雜基、 -CHC(0)Ci-C4坑氧基、C〇-4_ 總基-C(〇)雜 Ci_Cs燒基與 -CH2:：G<0)_R15-R16 ;而且，其Ci-C8烷基、c3-C6環烷 基V芳基-Co·4-燒基、雜芳基-C〇_4-垸基、胺基C1-C4 燒基、C3-C6環燒芳基基、芳基雜^^-^燒基、 -CHQCOCVC^烷氧基、CG.4-烷基·(：(0)雜Ci-Cs烷基與 -CH2_C(0)_R15-R16係各自獨立之未經取代或經由1 至3個各自獨立之選自R1 ’之取代基組成之群取代者 ;而且，其中之R15為Ο或NH，而R16為視情形之未 經取代或經由1至3個各自獨立之選自Rig，之取代基 組成之群取代之苄基； (b) R1’與R2’係各自獨立之由下列之基組成之群： 烷基、c^c：6環烷基、Cl_C5烷氧基、芳基C^C2烷氧基 、®基cvc成基、_基、芳基、C(0)(VC5燒基、·〇(〇)_ 芳基、_基(^-(：5烷基氧基、芳基Ci_C5烷基與二芳基 CrC5烷基；而且，其_c(〇)·芳基係未經取代或經由丄 至3個各自獨立之選自下列取代基組成之群取代者 :函基、c^c5烷基、函基心-^烷基、〇1_〇5烷氧基與 85504.doc -7- 200406371 -(^(COCrCs烷基；而且，其芳基Ci-C5烷基、二芳基 CVCs贫基與芳基係各自獨立之未經取代或經由1至3 — 個各自獨立之選自下列取代基組成之群取代者：自 -基、Ci-Cs燒基、芳基、鹵基C1-C5乾基、三鹵基C1-C3 - 烷基、Ci-Cs烷氧基與芳基C^-Cs烷基； (c) R2係選自下列取代基組成之群：C^-Cs烷基、C3-C6 環烷基、芳基-CG_4烷基、雜芳基-CG-4-烷基、雜 環烷芳基、雜(^-仏環烷芳基C1-C4烷基、胺基Cl-C4 了 基二C3_C6環芳基-Cg-2-彡充基、芳基雜Ci-Cs燒基、 C0-4-烷墓烷基、-CH(C(0)0CH3)苄基與 -CH2-C(0)-R15，，-R16” ；而且，其Cl-C8燒基、C3-C6 環烷基、芳基-Co·4-烷基、雜環烷芳基、雜Ci-C^ 環烷芳基C1-C4烷基、雜芳基-cG_4-烷基、胺基Ci-C^ 烷基、C^C：6環烷芳基_C〇_2_烷基、芳基雜(：1-(：8烷基、 C〇.4-fe 基 _C(0)雜 CVCs燒基與-CH2-C(0)-R15，，-R16，， 係各獨jl之未經取代或經由1至3個各自獨立之選-自R2’之取代基組成之群取代者； (d) R15”為 〇或 NH ; 一 (e) R16為未經取代或經由丨至3個各自獨立之選自ri6， 之取代基組成之群取代之；基； (f) R1與R2 一起可以形成雜環，該雜環係未經取代或經_ 由1土3個各自獨亙之選自R1，之取代基組成之群取 代者；〇R2 (a) R1 is selected from the group consisting of hydrogen, CVC8 alkyl, C3-C6 cycloalkyl, aryl-CG_4-alkyl, heteroaryl-CV4-alkyl, amino Ci- C ^ alkyl, C3-C6 cycloalkylaryl-C〇_2_alkyl, arylheteroyl, -CHC (0) Ci-C4 alkoxy, Co-4_total-C (〇) hetero Ci_Cs alkyl and -CH2 :: G < 0) _R15-R16; and Ci-C8 alkyl, c3-C6 cycloalkyl Varyl-Co · 4-alkyl, heteroaryl-C〇_4 -Fluorenyl, amine C1-C4 alkyl, C3-C6 cycloalkyl, aryl hetero ^^-^ alkyl, -CHQCOCVC ^ alkoxy, CG.4-alkyl · (:( 0) Hetero Ci-Cs alkyl and -CH2_C (0) _R15-R16 are each independently unsubstituted or substituted by a group consisting of 1 to 3 independent substituents selected from R1 '; and wherein R15 is 0 or NH, and R16 is unsubstituted or optionally substituted by a group consisting of 1 to 3 independent substituents selected from Rig; (b) R1 'and R2' are each independent The group consisting of the following groups: alkyl group, c ^ c: 6 cycloalkyl group, Cl_C5 alkoxy group, aryl C ^ C2 alkoxy group, ® group cvc group, _ group, aryl group, C (0) ( VC5 alkyl, 〇 (〇) _aryl, _ (^-(: 5 alkyloxy, aryl Ci_C5 alkyl, and diaryl CrC5 alkyl; further, its _c (〇) · aryl system is unsubstituted or through 丄 to 3 each independently selected from Substituents consisting of the following substituents: alkynyl, c ^ c5 alkyl, alkynyl- ^ alkyl, 〇__5 alkoxy and 85504.doc -7- 200406371-(^ (COCrCs alkyl; Moreover, its aryl Ci-C5 alkyl group, diaryl CVCs lean group and aryl system are each independently unsubstituted or substituted through 1 to 3 — each independently selected group consisting of the following substituents: from- Group, Ci-Cs alkyl group, aryl group, halo C1-C5 dry group, trihalo C1-C3-alkyl group, Ci-Cs alkoxy group and aryl C ^ -Cs alkyl group; (c) R2 series Is selected from the group consisting of the following substituents: C ^ -Cs alkyl, C3-C6 cycloalkyl, aryl-CG_4 alkyl, heteroaryl-CG-4-alkyl, heterocycloalkaryl, hetero (^ -Fluorene cycloalkaryl C1-C4 alkyl, amine Cl-C4 di-C3_C6 ring aryl-Cg-2-fluorenyl, aryl hetero-Ci-Cs alkyl, C0-4-alkylpentyl , -CH (C (0) 0CH3) benzyl and -CH2-C (0) -R15 ,, -R16 "; Moreover, its Cl-C8 alkyl group, C3-C6 cycloalkyl group, aryl-Co · 4 -Alkyl, heterocycloalkaryl, hetero Ci -C ^ cycloalkaryl C1-C4 alkyl, heteroaryl-cG_4-alkyl, amino Ci-C ^ alkyl, C ^ C: 6 cycloalkaryl_C〇_2_alkyl, aromatic Hexo (: 1-(: 8 alkyl, C.4-feyl_C (0) hetero CVCs alkyl and -CH2-C (0) -R15, -R16 ,, are each unique Substituted or substituted by 1 to 3 independent choices-a group consisting of substituents of R2 '; (d) R15 "is 0 or NH;-(e) R16 is unsubstituted or through 3 to 3 (F) R1 and R2 together can form a heterocyclic ring, the heterocyclic ring is unsubstituted or selected by three different groups A group consisting of substituents from R1;

(g) E係選自下列取代其^ J J a代基組成 < 群：c(R3)(r4)a、 85504.doc (CH2)nCOORl3、芳基-c0_4-烷基、硫基-CVCV烷基、 硫方基^方基Ci-C4燒氧基、Ci_C4fe氧基C1-C4燒基、 胺芳基與胺基烷基；而且，其（CH2)nCOOR13、 芳基-C(T4-燒基、硫基-Ci-Cr燒基、硫芳基、（VC4 烷氧芳基、CrC*烷氧基烷基、胺芳基與胺基(^.4 烷基係各自獨立之未經取代或經由1至3個各自獨立 之選自E’之取代基組成之群取代者； (h) R7’與R7”係各自獨立之選自CVC4烷基與CVC4鹵烷 基組成之群； (i) η與ιμ係各自獨立之選自〇、1、2與3組成之群； (j) Α係選自下列的基組成之群：（CH2)mCOOR14、 烷基腈、羧醯胺、磺胺、醯基磺胺與四唑，而且， 其績胺、醯基績胺與四峻係各自獨立之未經取代或 經由1至3個各自獨立之選自A，之取代基組成之群取 代者； (k) A’係j下列之基組成之群：Cl_c4烷基、Cl-C4鹵烷基 、雜i基與芳基，而且，其中該雜芳基與芳基係各 自獨立之未經取代或經由1至3個各自獨立選自下列 之取代基組成之群取代者，鹵基、烷基、C1-C5 鹵烷基、CVC5烷氧基與·CiCOCVCs烷基； (l) R3係選自下列的基組成之群：η、CVC5烷基、C1-C5 晞基與CrQ烷氧基； (m) R4係選自下列的基組成之群：η、鹵基、CVCs烷基 、Ci_66$元氧i基、衣燒基、芳基C〇-C4燒基與Cl-4 85504.doc -9- 200406371 烷氧芳基，而且，其CVC5烷基、CVC5烷氧基「 多衣丈元基Γ、方基C〇-C4fe基與Ci_4：fe氧芳基係各自獨立 之未經取代或各自獨立之經由1至4個各自獨立選自 R4之取代基組成之群取代者，或與R4係合併形成 C3-C6環烷基； (n) R5與R6係各自獨立之選自下列之基組成之群：氫、 cvc8烷基、芳基_c0_4-烷基、雜芳基_c〇_4-烷基、c3、C6 環烷芳基-C〇_2- k基、CVC6環烷基-C〇_2_烷基與〜 -CH2：^(0)-R17-R18 ;而且，其CVC8烷基、芳基_C(M_ 3馨 烷基、雜芳基-Cw烷基、CyC：6環烷芳基-CG_2-烷基、 C3-C6環烷基-CV2-烷基與-CH2-C(0)-R17_R18係各自 獨立之未經取代或經由1至3個各自獨立之選自R5， 之取代基組成之群取代者； (ο) E’、R4’、R5’與R13”係各自獨立之由下列之基組成 之群：C1-C5烷基、C1_C5烷氧基、C1-C5 iS烷基、C1-C5 鹵燒氧基、硝基、氰基、CHO、羥基、C1-C4燒酸、 〜 苯基、芳氧基、S02R7，、SR7，，、芳基C〇-2燒氧基、C1-C6 _ 烷叛醯胺基與COOH ; ’ (p) R16’係由下列的基組成之群··鹵基、Cl-C8烷基、芳 基、鹵燒基、三鹵Ci-Cs烷基、Ci_CV^氧基與芳基C^C5 、 烷基； (q) R17與R18係各自獨立選|Cl_C8烷基、芳基_ C〇y燒基 、雜芳基-C〇4_烷基、c3-c6環烷芳基{〇 2•烷基與匕-^ 環燒基-Cw燒基； 一 85504.doc -10 - 200406371 (〇 R13與R14係各自獨立選自下列之基組成之群：氫、 C1-C"^基、芳基與芳甲基，而且其C1-C4烷基係各 自獨亙之未經取代或各自獨立之經由1至3個各自獨 立之選自R13,之取代基組成之群取代者，而且其芳 甲基與芳基係各自獨立之未經取代或各自獨立之經 由1至3個各自獨立之選自R14，之取代基組成之群取 代者； (s) R13’係由下列之息組成之群：Ci-C5烷基、c^C6環烷 基、歹r_C5函烷基、Cl_Cs烷氧基、芳氧基、卣基、芳 基、-c(〜o)Cl-C5烷基、<(〇)-芳基、自基Ci_C5烷氧基 、芳基烷基與Cl_Cs烷二芳基，而且，其_c(〇)_ 芳基芳基、芳基Ci-C：5烷基與烷二芳基係各自 獨立之未經取代或經由1至3個各自獨立之選自R13 ” 之取代基組成之群取代者，與 ⑴R14’係由下列之基組成之群：_基、cl_c8烷基、Ci_c5 鹵燒#、CVC5烷氧基與芳基c〇_C4烷基，或 (U)其醫藥可接受之鹽。 本發明之-個具體實施例係針對由下列結構式所代表之 化合物： 式Γ(g) E is selected from the group consisting of the following substituted JJ a substituted group: group c (R3) (r4) a, 85504.doc (CH2) nCOORl3, aryl-c0_4-alkyl, thio-CVCV alkane Ci, C4-C4 alkyl, Ci_C4feoxy C1-C4 alkyl, amine aryl and amino alkyl; and (CH2) nCOOR13, aryl-C (T4-alkyl , Thio-Ci-Cr alkyl, thioaryl, (VC4 alkoxyaryl, CrC * alkoxyalkyl, aminearyl and amino groups (^ .4 alkyl groups are independently unsubstituted or via 1 to 3 substituents each independently selected from the group consisting of E '; (h) R7' and R7 "are each independently selected from the group consisting of CVC4 alkyl and CVC4 haloalkyl; (i) η And ιμ are each independently a group selected from the group consisting of 0, 1, 2 and 3; (j) A is a group selected from the group consisting of: (CH2) mCOOR14, alkyl nitrile, carboxamide, sulfonamide, fluorenyl Sulfa and tetrazole, and their amines, fluorenyl amines and tetramethylene are each independently unsubstituted or substituted through a group consisting of 1 to 3 independent substituents selected from A; (k) A 'is a group consisting of the following groups: Cl_c4 alkyl, Cl-C4 haloalkyl, heteroi group and Aryl, and wherein the heteroaryl and aryl are each independently unsubstituted or substituted through a group consisting of 1 to 3 substituents each independently selected from the group consisting of halo, alkyl, C1-C5 halo Alkyl, CVC5 alkoxy and CiCOCVCs alkyl; (l) R3 is a group selected from the group consisting of: η, CVC5 alkyl, C1-C5 fluorenyl, and CrQ alkoxy; (m) R4 is selected A group consisting of the following groups: η, halo, CVCs alkyl, Ci_66 $ oxo, alkynyl, aryl C0-C4, and Cl-4 85504.doc -9- 200406371 alkoxy aromatic Moreover, its CVC5 alkyl group, CVC5 alkoxy group, polyisopropyl group Γ, square group C0-C4fe group, and Ci_4: fe oxygen aryl group are each independently unsubstituted or each independently via 1 to 4 A group of substituents each independently selected from the group consisting of R4, or combined with R4 to form a C3-C6 cycloalkyl group; (n) a group of R5 and R6 each independently selected from the group consisting of hydrogen, cvc8 Alkyl, aryl_c0_4-alkyl, heteroaryl_c0_4-alkyl, c3, C6 cycloalkaryl-C0_2-k, CVC6 cycloalkyl-C〇_2_alkane And ~ -CH2: ^ (0) -R17-R18; and, its CVC8 alkyl, aryl_C (M_3 alkyl, heteroaryl-Cw alkyl, CyC: 6 cycloalkaryl-CG_2-alkyl, C3-C6 cycloalkyl-CV2-alkyl and -CH2-C (0) -R17_R18 series Each independently unsubstituted or substituted through a group consisting of 1 to 3 independent substituents selected from R5; (ο) E ', R4', R5 ', and R13 "are each independently a group consisting of Composition group: C1-C5 alkyl, C1-C5 alkoxy, C1-C5 iS alkyl, C1-C5 halooxy, nitro, cyano, CHO, hydroxyl, C1-C4 sulphuric acid, ~ phenyl, Aryloxy, S02R7 ,, SR7 ,,, aryl C0-2 alkoxy, C1-C6 _ alkylamine and COOH; '(p) R16' is a group consisting of the following groups ... Group, Cl-C8 alkyl, aryl, haloalkyl, trihalo Ci-Cs alkyl, Ci_CV ^ oxy and aryl C ^ C5, alkyl; (q) R17 and R18 are independently selected | Cl_C8 alkyl Aryl, aryl_Cy, alkynyl, heteroaryl-C04_alkyl, c3-c6 cycloalkaryl {〇2 alkyl and d-cycloalkyl-Cw alkyl;-85504. doc -10-200406371 (〇R13 and R14 are each independently selected from the group consisting of hydrogen, C1-C " ^, aryl and arylmethyl, and their C1-C4 alkyl Each group is independently unsubstituted or each is independently substituted by a group consisting of 1 to 3 independent substituents selected from R13, and its arylmethyl and aryl groups are independently unsubstituted or Each independently substituted by 1 to 3 independent groups consisting of R14; (s) R13 'is a group consisting of the following: Ci-C5 alkyl, c ^ C6 cycloalkyl歹 r_C5 alkyl, Cl_Cs alkoxy, aryloxy, fluorenyl, aryl, -c (~ o) Cl-C5 alkyl, < (〇) -aryl, Ci_C5 alkoxy, Arylalkyl and Cl_Cs alkyl diaryl, and its _c (〇) _ arylaryl, aryl Ci-C: 5 alkyl and alkyl diaryl are each independently unsubstituted or via 1 to Three independent groups consisting of substituents selected from R13 ", and ⑴R14 'are groups consisting of the following groups: _ group, cl_c8 alkyl group, Ci_c5 halogen group #, CVC5 alkoxy group and aryl group c __C4 alkyl, or (U) a pharmaceutically acceptable salt thereof. A specific embodiment of the present invention is directed to a compound represented by the following structural formula:

85504.doc -11 - 200406371 (a) R1係選自下列之基組成之群：氫、CVCs烷基、C3-C6 稼燒基^方基-C〇-4-燒基、雜芳基_C〇-4-燒基、胺基C1-C4 '坑基、C3" C6緣方基-Cq_2-纟充基、方基雜Ci_Cg健基、 ' -CHC(0)Ci_C4：fe 氧基、C〇.4_燒基-C(O)雜 Ci-Cg燒基與 . -CH2_C(0)-R15_R16，其中該CVC8烷基、C3_C6環烷基 、芳基-C〇-4-烷基、雜芳基-CG-4-烷基、胺基烷基 、〇3-0：6環烷芳基-Cw烷基、芳基雜匕-^烷基、 -CHC^C^CVC4烷氧基、Cw烷基-c(o)雜c!-c8烷基與 -CHy^^OhRlS-Rl6係各自獨立之視情形經由1至3個 ：^參 各自系立之選自R1，之取代基組成之群取代者；其中、 ，R15為Ο或NH，而R16為係視情形經由1至3個各自 獨立之選自R16’之取代基組成之群取代之苄基； (b) R2係選自下列之基組成之群：Cl-C8烷基、C3-C6環烷 基、芳基_CG·4·垸基、雜芳基-cG-4-燒基、胺基 烷基、C^C：6環烷芳基-Cw烷基、芳基雜(：1-(：8烷基、 C〇-4-烷基烷基與 _CH2-C(0)_R15-R16 ;其 中’'IICVQ烷基、c3-c6環烷基、芳基_c〇_4-烷基、雜 芳基-C〇-4-烷基、胺基Cl-C4烷基、（^(^環烷芳基_c w〜 烷基、芳基雜CVC8燒基、CG_4-燒基{⑼雜^仏烷基 與係各自獨立之視情形經由i至3 個各自獨立之選自R2,之取代基組成之群取代者；其 、 中，R15為0或NH，而R16為係視情形經由丨至3個各_ 自獨立之選自R16”之取代基組成之群取代之苄基； (c) R1與R2—起可以形成經取代或未經取代之雜環，·85504.doc -11-200406371 (a) R1 is a group selected from the group consisting of hydrogen, CVCs alkyl, C3-C6 alkyl, squaryl-C0-4-alkyl, heteroaryl_C 〇-4-Alkyl, amine C1-C4 'pit group, C3 " C6 marginal square group-Cq_2-fluorenyl group, square group hetero Ci_Cg phenyl group,' -CHC (0) Ci_C4: feoxy, C. .4-Calkenyl-C (O) heteroCi-Cgalkyl and .-CH2_C (0) -R15_R16, where the CVC8 alkyl, C3_C6 cycloalkyl, aryl-C0-4-alkyl, heteroaryl -CG-4-alkyl, aminoalkyl, 0-3-0: 6 cycloalkaryl-Cw alkyl, arylhetero-alkyl, -CHC ^ C ^ CVC4 alkoxy, Cw alkyl The groups -c (o) heteroc! -C8 alkyl and -CHy ^^ OhRlS-Rl6 are independently independent through 1 to 3 as appropriate: ^ Respectively, each group is substituted by a group consisting of substituents selected from R1 Where, R15 is 0 or NH, and R16 is a benzyl group substituted by a group consisting of 1 to 3 independent substituents selected from R16 ', as appropriate; (b) R2 is a group selected from the following Composition group: Cl-C8 alkyl, C3-C6 cycloalkyl, aryl_CG · 4 · fluorenyl, heteroaryl-cG-4-alkyl, aminoalkyl, C ^ C: 6 cycloalkane Aryl-Cw alkyl, aryl hetero (: 1-(: 8 alkyl, C 〇-4-alkylalkyl and _CH2-C (0) _R15-R16; where `` IICVQ alkyl, c3-c6 cycloalkyl, aryl_c〇_4-alkyl, heteroaryl-C 〇-4-alkyl, amine Cl-C4 alkyl, (^ (cycloalkylaryl_cw ~ alkyl, aryl hetero CVC8 alkyl, CG_4-alkyl) Independently, through i to 3 independent group substitutions consisting of substituents selected from R2, where, R15 is 0 or NH, and R16 is dependent on the situation through 丨 to 3 each A benzyl group substituted by a group consisting of a substituent selected from R16 "; (c) R1 and R2 together may form a substituted or unsubstituted heterocyclic ring, ·

(d) E係選自由下列之基組成之群·· c(R3)(R4)a與經取代J 85504.doc -12· 200406371 或未經取代之選自下列之基組成之群··（CH2)nCOOR13 、方基^lCg_4-燒基、硫基-C1-C4-祝基、硫芳基、C1-C4 ^元氧方基、Ci_C4乾氧基Ci_C4：fe基、胺芳基與胺基 CVC4烷基； (e) η與m係各自獨立選自〇、1、2與3組成之群； (f) A係選自由下列的基組成之群之官能基： (CH2)mCOOR14、（VC3烷基腈、羧醯胺、經取代或未 經取代之續胺、攀取代或未經取代之醯基續胺與經 取代或未經取代之四也； (g) R3係Ή、〜飽和或不飽和之基、C1-C5燒氧基； (h) R4係Η、鹵基、選自下列之經取代或未經取代之Ci_c5 fe基、CrCs燒氧基、C3-C6環燒基、芳基c〇-C4燒基、 CV4烷氧芳基與苯基，或R3與R4係合併形成c3-cy| 燒基； (i) R5與R6係各自獨立之選自下列之基組成之群··氫、 選自下列之經取代或未經取代之CrC8烷基、芳基 -◦〇-4^丨充棊、雜芳基-C〇-4-燒基、〇3-(^6環燒芳基_C〇2_ 火元基、C3_C6^fe 基- C〇.2-fe 基與- CH2_C(0)-R17-R18 · (j) R17與R18係各自獨立之選自CVC8烷基、芳基_C(M、 烷基、雜芳基-Cw-烷基、C^C：6環烷芳基-Cw-烷基與 Cs-Cp衣規基- C〇-2"·故基； (k) R13與R14係各自獨立之選自下列之基組成之群：氧 、視情形經取代之C1-C4烷基與視情形經取代之芳甲 基’及其醫藥可接受之鹽。 本發明之另一個具體實施例係式II化合物： -13- 85504.doc 200406371(d) E is selected from the group consisting of: c (R3) (R4) a and substituted J 85504.doc -12 · 200406371 or an unsubstituted group consisting of: CH2) nCOOR13, square group ^ Cg_4-alkyl, thio-C1-C4-yl, thioaryl, C1-C4 oxo square group, Ci_C4 dry oxygen Ci_C4: fe group, amine aryl group and amine group CVC4 alkyl; (e) η and m are each independently selected from the group consisting of 0, 1, 2 and 3; (f) A is a functional group selected from the group consisting of: (CH2) mCOOR14, (VC3 Alkyl nitriles, carboxamidamines, substituted or unsubstituted amines, substituted or unsubstituted fluorenyl amines, and substituted or unsubstituted tetramines; (g) R3 is Ή, ~ saturated or Unsaturated group, C1-C5 alkoxy group; (h) R4 series fluorene, halo group, substituted or unsubstituted Ci_c5 fe group, CrCs alkoxy group, C3-C6 cycloalkyl group, aromatic group C0-C4 alkyl, CV4 alkoxyaryl and phenyl, or R3 and R4 are combined to form c3-cy | alkyl; (i) R5 and R6 are each independently a group selected from the group consisting of: · Hydrogen, substituted or unsubstituted CrC8 alkyl group, aryl group -◦〇-4 ^ 丨Fluorene, heteroaryl-C〇-4-alkynyl, 〇3-(^ 6cycloalkynyl_C〇2_ fire group, C3_C6 ^ fe group-C.2-fe group and -CH2_C (0) -R17-R18 (j) R17 and R18 are each independently selected from CVC8 alkyl, aryl_C (M, alkyl, heteroaryl-Cw-alkyl, C ^ C: 6 cycloalkaryl- Cw-alkyl and Cs-Cp glycosyl-C〇-2 " • base; (k) R13 and R14 are each independently a group selected from the group consisting of oxygen, optionally substituted C1-C4 Alkyl and optionally substituted arylmethyl 'and pharmaceutically acceptable salts thereof. Another embodiment of the present invention is a compound of formula II: -13- 85504.doc 200406371

其中，R19係選自下列之基組成之群：氫、CrCU烷基、 芳基與芳甲基，其中該烷基、芳基與芳甲基係未經取代或 經由1至3個各自獨立之選自R14’之取代基組成之群所取Among them, R19 is selected from the group consisting of hydrogen, CrCU alkyl, aryl, and arylmethyl, wherein the alkyl, aryl, and arylmethyl are unsubstituted or separated by 1 to 3 each Selected from the group consisting of substituents of R14 '

代者， 及其醫藥可接受之鹽，其中，Rl、R2、R3、R4、R5與R6 係如上述式I >斤定義者。 本發明之另一個具體實施例係式III化合物： 〇Generation, and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R5 and R6 are those defined by the formula I > Another embodiment of the present invention is a compound of formula III: 〇

其中，R19係選自下列之基組成之群：氫、C1-C4烷基、 芳基與芳甲基，其中該烷基、芳基與芳甲基係未經取代 或經由1至3個各自獨立之選自R14’之取代基組成之群所 取代者， 及其醫藥可接受之鹽；其中，IU、R2、R3、R4、R5與R6 係如上述式I所定義者。 本發明之另一個具體實施例係下列結構式之化合物及其 醫藥可接受之鹽： 85504.doc -14-Among them, R19 is selected from the group consisting of hydrogen, C1-C4 alkyl, aryl, and arylmethyl, wherein the alkyl, aryl, and arylmethyl are unsubstituted or passed through 1 to 3 each Those independently selected from the group consisting of substituents R14 ′, and pharmaceutically acceptable salts thereof; wherein IU, R2, R3, R4, R5 and R6 are as defined in the above formula I. Another embodiment of the present invention is a compound of the following structural formula and a pharmaceutically acceptable salt thereof: 85504.doc -14-

200406371 其中，R11係選自下列之基組成之群：芳基、芳氧基、_c(〇) 芳基、鹵基C^C：5烷氧基、烷芳基、C!-C5烷二芳基與 CVC6烷基，其中該芳基、-c(o)芳基、鹵基Cl-C5烷氧基、 CVC5燒芳基一、Ci-C5燒二芳基與C^C：6燒基係各自獨立之未 經取代或各自-獨立之經由1至3個各自獨立之選自Ri，之取 代基組成之群取代者。 本發明之另一個較佳具體實施例係下列結構式之化合物 及其醫藥可接受之鹽：200406371 Among them, R11 is selected from the group consisting of aryl, aryloxy, _c (〇) aryl, halo C ^ C: 5 alkoxy, alkaryl, C! -C5 alkanediaryl And CVC6 alkyl, where the aryl, -c (o) aryl, halo Cl-C5 alkoxy, CVC5 aryl one, Ci-C5 diaryl and C ^ C: 6 alkynyl Each independently unsubstituted or each-independent is replaced by a group consisting of 1 to 3 independent substituents selected from Ri and Ri. Another preferred embodiment of the present invention is a compound of the following structural formula and a pharmaceutically acceptable salt thereof:

其中，R12係選自下列之基組成之群，芳基、芳氧基、_c(〇) 芳基、鹵基C1-C5坑氧基、芳基CrCs燒基、CrCs燒二芳基 與(^-(：6烷基，其中該芳基、-C(O)芳基、芳氧基、鹵基 烷氧基、C「C5烷芳基、烷二芳基與烷基係各自 獨立之未經取代或各自獨立之經由1至3個各自獨立之選自 R1，之取代基組成之群所取代者。 85504.doc -15- 200406371 另一個具體實施例係下式之化合物：Among them, R12 is selected from the group consisting of aryl, aryloxy, _c (〇) aryl, halo C1-C5 pitoxy, aryl CrCs alkyl, CrCs diaryl, and (^ -(: 6 alkyl group, wherein the aryl group, -C (O) aryl group, aryloxy group, haloalkoxy group, C5 alkylaryl group, alkyldiaryl group and alkyl group are each independently Substituted or independently substituted by a group consisting of 1 to 3 independent substituents selected from R1. 85504.doc -15- 200406371 Another embodiment is a compound of the formula:

,R12 在本發明之另一個特徵，其將本文申請專利範圍之化合, R12 is another feature of the present invention, which combines

物放射標定。 ' 在一個具 _體實施例，本發明亦係有關包括至少一種本發 明化合物，—或其醫藥可接受之鹽及醫藥可接受載體之醫藥 組合物。 在另一個具體實施例，本發明係有關令PPARa受體與至 少一種由結構式I所代表之化合物與/或其醫藥可接受之鹽 接觸，而調節該受體之方法。Object radiation calibration. In one embodiment, the invention also relates to a pharmaceutical composition comprising at least one compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another embodiment, the present invention relates to a method for modulating a PPARa receptor by contacting it with at least one compound represented by Formula I and / or a pharmaceutically acceptable salt thereof.

在另一個具體實施例，本發明係有關令ΡΡΑΓΙγ受體與至少 一種由結構式I所代表之化合物與/或其醫藥可接受之鹽接 觸，而調節該受體之方法。 在另一個具體實施例，本發明係有關令ΡΡΑΙΙδ受體與至 少一種由結構式I所代表之化合物與/或其醫藥可接受之鹽 接觸，而調節該受體之方法。 在另一個具體實施例，本發明係有關令PPARa受體以及 ΡΡΑΓΙγ受體與至少一種由結構式I所代表之化合物與/或其 醫藥可接受之鹽接觸，而調節該受體之方法。In another specific embodiment, the present invention relates to a method for modulating a PPAΓΙγ receptor by contacting it with at least one compound represented by Formula I and / or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to a method for modulating a PPAIIII receptor by contacting at least one compound represented by Formula I and / or a pharmaceutically acceptable salt thereof. In another specific embodiment, the present invention relates to a method for modulating the PPARa receptor and the PPAIΓγ receptor by contacting at least one compound represented by Formula I and / or a pharmaceutically acceptable salt thereof.

在另一個具體實施例，本發明係有關令ΡΡΑΙΙγ以及PPARS 85504.doc -16- 200406371 受體與至少一種由結構式I所代表之化合物與/或其醫藥可 接受之鹽接翁^，而調節該受體之方法。In another specific embodiment, the present invention relates to the regulation of PPAIIII and PPARS 85504.doc -16- 200406371 receptors and at least one compound represented by Formula I and / or a pharmaceutically acceptable salt thereof, and regulates The receptor method.

本發明化合物可有效治療、與對於易罹患之病患預防X 症候群、第二型糖尿病、高血糖症、高脂血症、肥胖症、 凝血病變、高血壓、動脈粥狀硬化、及其他與X症候群相關 之病症與心血管疾病。此外，經預期該化合物比目前用以 治療這些病情之化合物具更佳之臨床安全性與效率情形。 甚且，本發明化合物可用以降低凝血纖維酶原、增加HDL 量、治療腎%臟病、控制所需之體重、治療髓鞘脫失性疾病 、治療某些病毒感染與治療肝病。 【實施方式】 本發明所用之說明用語具有如下意義。The compounds of the present invention are effective in treating and preventing Symptoms X, Type 2 diabetes, hyperglycemia, hyperlipidemia, obesity, coagulopathy, hypertension, atherosclerosis, and others related to X. Syndrome-related disorders and cardiovascular disease. In addition, the compound is expected to have better clinical safety and efficiency profiles than the compounds currently used to treat these conditions. Furthermore, the compounds of the present invention can be used to reduce coagulogen, increase the amount of HDL, treat kidney viscera, control the required body weight, treat demyelinating diseases, treat certain viral infections and treat liver diseases. [Embodiment] The explanatory terms used in the present invention have the following meanings.

當使用於本文時，“烷基”包括完全飽和之直鏈與/或支鏈 烴。“CG-Cn，烷基”之用語意指具所述碳原子數之烷基。在本 發明之一個較佳具體實施例，較佳之c〇-cn，烷基為甲基、乙 基、丙基或基。另一較佳之q-Q烷基為甲基或乙基。 當使用於I文時，“胺基C1-C4烷基”之用語意指該胺基係 經由具所述碳原子數之烷基連接於鹼分子。 “-c(o)烷基”之用語意指該具所述碳原子數之烷基係經 由“-C(O)-”連接子連接於鹼分子。依此，_C(0)C1-C5烷基意 指經由-C(O)連接子連接於該鹼分之具有由1至5個碳原子 之烷基。 當使用於本文時，“烯基”為至少具有1個雙鍵之不飽和之 Ci-Cs直鏈與/或支鏈烴基。 85504.doc -17- 200406371 當使用於本文時，“環烷基”與“c3-c6環烷基”包括部分或 完全飽和之其~有所述碳原子數且為環狀之環狀烴。該環烷 基以完全飽和較佳。若該環烷基為具c3-c7烷基之環可能更 佳。此類環烷基包括但不限於環丙基、環戊基或環己基， 及其類似物。 當使用於本文時，“芳基”之用語包括羰環芳香環系統（例 如，苯基）、融合之多環芳香環系統（例如莕與蒽基）與融合 於羰環非芳香環系統之每香環系統（例如，1，2,3,4-四氫莕基 與苯并二崎#•基）。較佳之芳基為苯基。當使用於本文時， “芳烷基”意指钕芳基係經由具所述碳原子數之烷基連接子 連接於附著點者。該烷基若為C0-C3或C1-C3烷基可能較佳 。“芳基-C〇烷基”之用語意指該芳基係經由一個鍵結直接連 接於附著點。當使用於本文時，“烷芳基”與“C1-C5烷芳基” 之用語亦意指該芳基係經由具所述碳原子數之烷基連接子 連接於附著點者。該烷基連接子以具有1至3個碳原子較佳 。較佳之@可以為C6-C10芳基。“芳甲基”之用語意指為 芳基(^烷基之芳烷基。 當使用於本文時，“芳基取代基”之用語具有如本文上述 定義之“芳基’’之相同意義。“-C(O)芳基取代基”之用語意指 該芳基係經由-C(O)-連接子連接於鹼分子。甚且，當使用於 本文時，“-C(O)芳基”之用語具有如“-C(O)芳基取代基”相同 之意義。 當使用於本文時，“芳氧基”之用語意指該芳基係經氧連 接於驗分子。 85504.doc -18- 200406371 當使用於本文時，“Cl-C5烷二芳基”之用語意指具所述碳 原子數之烷塞'係連接於鹼分子，而且，在該烷基終端係經 兩個獨立之芳基所取代。在一較佳具體實施例，該二芳基 之每個芳基為苯基較佳。As used herein, "alkyl" includes fully saturated linear and / or branched hydrocarbons. The term "CG-Cn, alkyl" means an alkyl group having the stated number of carbon atoms. In a preferred embodiment of the present invention, the preferred co-cn is alkyl, methyl, ethyl, propyl or aryl. Another preferred q-Q alkyl is methyl or ethyl. When used in the text, the term "amino C1-C4 alkyl" means that the amine group is connected to a base molecule via an alkyl group having the carbon number. The term "-c (o) alkyl" means that the alkyl group having the carbon number is connected to a base molecule via a "-C (O)-" linker. Accordingly, _C (0) C1-C5 alkyl means an alkyl group having 1 to 5 carbon atoms connected to the base via a -C (O) linker. As used herein, "alkenyl" is an unsaturated Ci-Cs straight-chain and / or branched hydrocarbon group having at least one double bond. 85504.doc -17- 200406371 As used herein, "cycloalkyl" and "c3-c6 cycloalkyl" include partially or fully saturated cyclic hydrocarbons having the number of carbon atoms mentioned and cyclic. The cycloalkyl group is preferably fully saturated. It may be better if the cycloalkyl group is a ring having a c3-c7 alkyl group. Such cycloalkyls include, but are not limited to, cyclopropyl, cyclopentyl, or cyclohexyl, and the like. As used herein, the term "aryl" includes each of a carbonyl ring aromatic ring system (e.g., phenyl), a fused polycyclic aromatic ring system (e.g., fluorene and anthracenyl), and a Fragrant ring systems (for example, 1,2,3,4-tetrahydrofluorenyl and benzodiazine # • yl). A preferred aryl group is phenyl. As used herein, "aralkyl" means a neodymyl group connected to an attachment point via an alkyl linker having the stated number of carbon atoms. The alkyl group may be a C0-C3 or C1-C3 alkyl group. The term "aryl-C0 alkyl" means that the aryl group is directly connected to the attachment point via a bond. As used herein, the terms "alkaryl" and "C1-C5 alkaryl" also mean that the aryl group is connected to the attachment point via an alkyl linker having the stated carbon number. The alkyl linker preferably has 1 to 3 carbon atoms. Preferably, @ may be C6-C10 aryl. The term "arylmethyl" means an arylalkyl group. When used herein, the term "aryl substituent" has the same meaning as "aryl" as defined herein above. The term "-C (O) aryl substituent" means that the aryl group is connected to the base molecule via a -C (O)-linker. Even when used herein, "-C (O) aryl group The term "" has the same meaning as "-C (O) aryl substituent". As used herein, the term "aryloxy" means that the aryl group is attached to the test molecule via oxygen. 85504.doc- 18- 200406371 As used herein, the term "Cl-C5 alkanediaryl" means that the alkane plug having the number of carbon atoms described above is connected to a base molecule, and that the alkyl terminal is connected via two independent The aryl group is substituted. In a preferred embodiment, each aryl group of the diaryl group is preferably a phenyl group.

“環烷芳基”之用語意指與芳基融合形成二環取代基之環 烷基。環烷芳烷基意指該融合之雙環環烷芳基係經由烷基 連接子連接於鹼分子。亦即，“C3-C6環烷芳基-C0-C2烷基” 意指具有3至6個碳原子之環烷基係與芳基融合，然後，經 由具0至2個_^舞原子之烷基連接於鹼分子。當所具之碳原子 為0，則該芳ί係直接連接於鹼分子。The term "cycloalkaryl" means a cycloalkyl group fused to an aryl group to form a bicyclic substituent. Cycloalkaryl means that the fused bicyclic cycloalkaryl is connected to the base molecule via an alkyl linker. That is, "C3-C6 cycloalkaryl-C0-C2 alkyl" means that a cycloalkyl system having 3 to 6 carbon atoms is fused with an aryl group, and then, via a group having 0 to 2 An alkyl group is attached to a base molecule. When the carbon atom is 0, the aromatic group is directly connected to the alkali molecule.

“鹵基’’之用語意指Cl、F、Βι:與I。較佳之鹵基為C1。另一 個較佳之鹵基為F。當使用於本文時，“C1-C4鹵烷基”與“鹵 基C1-C4烷基”意指該具有所述碳原子數之烷基，可以經一 或多個鹵素所取代。例如，但不限於CF3、C2H5、C2F3、C3H7 及其類似物。類此，“鹵基C1-C5烷氧基”之用語意指經一或 多個鹵基戶0又代之具所述碳原子數之烷氧基。該i烷氧基 係經由氧連接於驗分子。 當使用於本文時，“雜芳基”包括羰環芳香環系統，其中 該芳基之至少一個碳係經至少一個獨立選取之諸如氮、氧 或硫之雜原子所取代（例如，吡錠基及其類似物），融合之多 環芳香環系統具有至少一個取代環上之碳之雜原子，而融 合於羰環非芳香環系統之芳香環系統具有至少一個取代環 上之碳之雜原子。較佳之雜芳基可以為C5-C10雜芳基。較 佳之雜芳基為硫苯基、喻錠基、喊淀基、批_基及其類似 85504.doc -19- 200406371 物。另一較佳雜芳基為p号吐基、p塞嗤基及其類似物。另一 較佳雜芳基為Γ噻吩基、嘧唑基、苯并嘧唑基、噻二唑基及 其類似物。 當使用於本文時，“雜芳基-c〇-cn烷基”之用語意指該雜芳 基係經具所述碳原子數之烷基連接於鹼分子。當使用於本 文時，“雜芳基Co烷基”之用語意指該雜芳基係直接連接於 驗分子。The term "halo" means Cl, F, Beta: and I. A preferred halo is C1. Another preferred halo is F. As used herein, "C1-C4 haloalkyl" and " "Halo C1-C4 alkyl" means that the alkyl group having said carbon number can be substituted with one or more halogens. For example, but not limited to CF3, C2H5, C2F3, C3H7 and the like. The term "halo C1-C5 alkoxy" means an alkoxy group having the stated number of carbon atoms replaced by one or more halo groups. The i-alkoxy group is connected to the test molecule via oxygen. As used herein, "heteroaryl" includes a carbonyl ring aromatic ring system in which at least one carbon of the aryl group is replaced by at least one independently selected heteroatom such as nitrogen, oxygen, or sulfur (e.g., pyridinium Radicals and their analogs), the fused polycyclic aromatic ring system has at least one heteroatom of carbon substituted on the ring, and the aromatic ring system fused to the carbonyl ring non-aromatic ring system has at least one substituted carbon heteroatom .The preferred heteroaryl group may be a C5-C10 heteroaryl group. The preferred heteroaryl group is a thiophenyl group, a hydrazone group, And other similar aryl groups such as 85504.doc -19-200406371. Another preferred heteroaryl group is p-tolyl, p-acetyl, and the like. Another preferred heteroaryl is Γ thienyl. , Pyrazolyl, benzopyrazolyl, thiadiazolyl, and the like. As used herein, the term "heteroaryl-c0-cnalkyl" means that the heteroaryl group is a chemical compound. The carbon number alkyl group is connected to the base molecule. As used herein, the term "heteroaryl Co alkyl group" means that the heteroaryl group is directly connected to the test molecule.

當使用於本文時，“C0_4烷基<(0)雜(^-€：8烷基”之用語意 指其中一個_舞原子係經選自包括S、Ο與N之雜原子之群所 取代之雜仏^“完基，係經由CG_4-烷基C(O)基連接於鹼之核 。具體實施例包括，但不限於該雜烷基為甲氧基、乙氧基 、丙氧基及其類似物者。 當使用於本文時，“C1-C5烷氧基”或“Cl-Cn’烷氧基’’之用 語意指該具所述碳原子數之烷基，係經氧連接於鹼分子。As used herein, the term "C0_4 alkyl < (0) hetero (^-€: 8 alkyl") means that one of the atom is selected from the group consisting of hetero atoms including S, O and N Substituted heteroalkyl radicals are connected to the core of the base via a CG_4-alkyl C (O) group. Specific examples include, but are not limited to, the heteroalkyl groups are methoxy, ethoxy, and propoxy When used herein, the terms "C1-C5 alkoxy" or "Cl-Cn'alkoxy" mean the alkyl group having the stated carbon number, which is connected via oxygen In base molecules.

當使用於本文時，“-CHC(0)C1-C4烷氧基’’之用語意指該 具所述碳原j數之烷氧基，係經-CH-C(O)-連接子連接於鹼 分子。據此，“-CH2C(0)R15-R16”之用語意指該R16係經 “·CH2C(0)R15”連接子連接於鹼分子。 當使用於本文時，“芳基雜C^-Cs烷基”之用語意指該芳基 係經由其中該烷基之一個碳原子係經選自包括S、Ο與N之 雜原子組成之群所取代之CrCs烷基而連接於鹼核。具體實 施例之一係當該雜原子為S，則該芳基為未經取代或經由1 至3個各自獨立之選自PHENYLSUB組成之取代基所取代之 苯基。另外一個具體實施例係當該雜原子為Ο，則該芳基為 85504.doc -20- 200406371 未經取代或經1至3個各自獨立之選自PhenYLSUB組成之 取代基組成之群所取代之苯基。另一個具體實施例係當該 雜原子為N，則該芳基為未經取代或經1至3個各自獨立之選 自PHENYLSUB組成之取代基組成之群所取代之苯基。當使 用於本文時’ PHENYLSUB”係由鹵基、C1-C8燒基、芳基 、鹵基CrC：3烷基、三鹵基C1_C3烷基、Ci-C3烷氧基、 ^(COCi-C4烷基與芳基烷基組成之群。 當使用於本文時，“雜環基，，或“雜環，，為具所述碳原子數 之Cs-Ci2環色統，其中，由1至3個碳原子係經諸如氮、硫或 ~* 氧之雜原子所取代。雜環基包括苯并呋喃基、苯并嘧唑基 、苯并嘧吩基、異喹啉基、異呤唑基、嗎福啉基、嘮二吐 基、吡啶基、嘧啶基、吡咯基、喳啉基、四氫哌喃基與嘧 吩基。該雜環基為3至6環可能較佳。As used herein, the term "-CHC (0) C1-C4 alkoxy" means that the alkoxy group having the carbon number j is connected via a -CH-C (O)-linker Based on this, the term "-CH2C (0) R15-R16" means that the R16 is connected to the base molecule via a "· CH2C (0) R15" linker. As used herein, "aryl heterocyclic The term "C ^ -Csalkyl" means that the aryl group is attached to the base via a carbon atom system in which the alkyl group is substituted with a CrCs alkyl group selected from the group consisting of heteroatoms including S, O, and N. One of the specific examples is that when the heteroatom is S, the aryl group is unsubstituted or substituted by 1 to 3 independent substituents selected from the group consisting of PHENYLSUB. Another specific embodiment When the heteroatom is 0, the aryl group is 85504.doc -20-200406371 unsubstituted or substituted by 1 to 3 groups each independently selected from the group consisting of PhenYLSUB. Another The specific embodiment is that when the heteroatom is N, the aryl group is unsubstituted or substituted with 1 to 3 groups each independently selected from the group consisting of PHENYLSUB Phenyl. When used herein, "PHENYLSUB" refers to halo, C1-C8 alkyl, aryl, halo CrC: 3 alkyl, trihalo C1-C3 alkyl, Ci-C3 alkoxy, ^ (COCi -C4 alkyl and arylalkyl group. As used herein, "heterocyclyl," or "heterocyclic," is a Cs-Ci2 ring chromosome with the stated number of carbon atoms, where Up to 3 carbon atoms are replaced by heteroatoms such as nitrogen, sulfur, or ~ * oxygen. Heterocyclyls include benzofuranyl, benzopyrazolyl, benzopyrimyl, isoquinolinyl, isoxurazole Group, morpholinyl group, pyridixyl group, pyridyl group, pyrimidinyl group, pyrrolyl group, fluorinyl group, tetrahydropiperanyl group and pyrimidinyl group. The heterocyclic group may have 3 to 6 rings.

與/或 較佳之雜環可能為 “雜環燒芳基”之用語意指如上定義之雜環基係融合於芳 基以形成該取代基。此類基包括，但絕對不限於：The term and / or preferred heterocycle may be "heterocyclic aryl" means that a heterocyclic group as defined above is fused to an aryl group to form the substituent. Such bases include, but are not limited to:

及其類似物。雜環烷芳烷基之用語意指該雜環烷芳基係經 具所述碳原子數之烷基連接於鹼分子。因此雜<：1-(：6環燒芳 85504.doc -21- 200406371 基C1-C4烷基係為與芳基融合並經由C1-C4烷基連接子連接 於鹼分子之&T-C6雜環。較佳之芳基為苯基。 “硫芳基”之用語意指該芳基具有至少一個經硫原子取代 之碳原子。此類硫芳基包括，但不限於硫苯基及其類似物。 “烷氧芳基”之用語意指該芳基係經烷氧基連接子附著於 鹼分子。“烷氧烷基”之用語意指該烷基鏈具有一個經氧原 子取代之碳原子。“胺芳基”之用語意指該芳基係經胺基連 接於鹼分子。“胺烷基”之用語意指該烷基鏈係經胺基附著 於鹼分子。，烷基腈”之用語意指該 基係經烷基連接子附 著於鹼分子。~ 結構式I化合物可能含一或多個對掌中心，並存在不同光 學活性型式。當結構式I化合物含一個對掌中心時，該化合 物存在兩個對掌異構物型式；而且，本發明包括對掌體與 諸如消旋混合物之對掌體之混合物。該對掌體可利用熟諳 此意者熟知之方法解旋，例如藉例如結晶以形成可分離之 立體異構物鹽，例如藉結晶、氣液相或液相層析形成可分 ~ 一 離之立體異構物衍生物或錯合物，令對掌體與對掌體專一 性試劑進行例如酶酯化之選擇性反應，或在例如具有結合 之對掌配位體之矽膠或在含對掌性溶劑條件之對掌體支持 之對掌性環境進行氣液或液相層析。應了解，在利用上述 之一種分離方法將所需對掌體轉化成另一種化學成份時， 需要進一部之步驟以釋放所需之對掌體型式。替代地，可 藉不對稱性合成，利用光學活性試劑、受質、催化劑或溶 劑，或藉非對稱轉型將一種對掌體轉化成另一種以合成特 85504.doc -22- 200406371 定對掌體。 當結構式t代表之化合物具有一個以上之對掌體取代基 時，其可能存在立體異構物型式。該立體異構物對可藉熟 諳此藝者已知之方法，例如層析或結晶加以分離；而每一 對中之個別對掌體亦可如上述加以分離。本發明包括結構 式I化合物之每一個立體異構物及其混合物。And its analogs. The term heterocycloalkaryl means that the heterocycloalkaryl group is connected to a base molecule via an alkyl group having the above-mentioned carbon number. Therefore, the hetero- <: 1-(: 6-ringed aromatic aryl 85504.doc -21- 200406371 group C1-C4 alkyl system is fused to an aryl group and connected to a base molecule via a C1-C4 alkyl linker & T- C6 heterocycle. Preferred aryl is phenyl. The term "thioaryl" means that the aryl has at least one carbon atom substituted with a sulfur atom. Such sulfur aryl groups include, but are not limited to, thiophenyl and its Analogs. The term "alkoxyaryl" means that the aryl is attached to a base molecule via an alkoxy linker. The term "alkoxyalkyl" means that the alkyl chain has a carbon substituted with an oxygen atom Atom. The term "amine aryl" means that the aryl group is connected to a base molecule via an amine group. The term "amine alkyl" means that the alkyl chain is attached to a base molecule via an amine group. "Alkyl nitrile" The term means that the group is attached to the base molecule via an alkyl linker. ~ The compound of structural formula I may contain one or more palm centers and different optically active forms. When the compound of structural formula I contains a palm center There are two types of palmar isomers of the compound; moreover, the present invention includes mixing palmar with A mixture of opposite palms. The pair of palms can be unwound by methods well known to those skilled in the art, such as by crystallization to form separable stereoisomer salts, such as by crystallization, vapor phase, or liquid phase. Separation to form a detachable stereoisomeric derivative or complex, allowing selective reaction between palm body and palm body-specific reagents, such as enzymatic esterification, or coordination such as binding Gas-liquid or liquid chromatography of the palm of the body or in a palm environment with palm support in the presence of palm solvent conditions. It should be understood that one of the separation methods described above is used to convert the palm of the body into another In the case of chemical composition, a further step is required to release the desired palm type. Alternatively, it can be synthesized by asymmetric synthesis, using optically active reagents, substrates, catalysts or solvents, or by asymmetric transformation It can be converted into another antagonism by synthesis of 85504.doc -22-200406371. When the compound represented by the structural formula t has more than one antagonism substituent, it may have a stereoisomeric form. The stereoisomer Structure It can be separated by methods known to those skilled in the art, such as chromatography or crystallization; and the individual palms of each pair can also be separated as described above. The present invention includes each stereoisomer of the compound of formula I and Its mixture.

結構式I之某些化合物可存在可分離之不同安定構型。因 為有關不對稱性單鍵之受限的旋轉，例如因為立體阻隔或 環之張力之%扭轉之不對稱性，可允許不同構型體之分離。 本發明包括結〗冓式I化合物之每個構型異構物及其混合物。 結構式I之某些化合物可存在兩性離子型式，而且，本發 明包括結構式I化合物之每個兩性離子型式及其混合物。 “醫藥可接受之鹽類”針對實質對哺乳動物無毒性之結構 式I之化合物之鹽。典型的醫藥可接受之鹽包括，那些藉本 發明化合物與礦物性或有機酸或有機或無機鹼反應製備之Certain compounds of formula I may exist in different stable configurations that are separable. Due to the restricted rotation of the asymmetric single bond, for example because of the asymmetry of steric block or% twist of the ring tension, separation of different configurations can be allowed. The invention includes each conformational isomer of compounds of formula I and mixtures thereof. Certain compounds of formula I may exist in zwitterionic form, and the invention includes each zwitterionic form of compounds of formula I and mixtures thereof. "Pharmaceutically acceptable salts" are directed to salts of compounds of Formula I that are substantially non-toxic to mammals. Typical pharmaceutically acceptable salts include those prepared by reacting a compound of the present invention with a mineral or organic acid or an organic or inorganic base

鹽。此類聲_分別為已知之鹼加成鹽。應了解，只要該鹽整 一 體性為醫藥可接受，而且只要該反離子對該鹽之整體並未 貢獻不必要之性質，則形成本發明之任何鹽之一部分之特 定的反離子之特性並不重要。 因為其酸部分，結構式I化合物會與醫藥可接受之鹼形成 鹽。某些驗加成鹽之實例包括諸如之金屬鹽，諸如4里、 鈉、鉀之鹼金屬鹽，與諸如鈣與鎂之鹼土金屬鹽，與銨或 經取代之銨鹽。經取代之銨鹽之實例包括例如，那些與諸 如三甲胺、三乙胺之低碳烷胺形成者，諸如2-羥乙胺、雙-(2- 85504.doc -23- 200406371 羥乙基）-胺或三-(2-羥乙基）-胺之羥烷胺，諸如二環己胺或 二苄基哌啶之—環烷胺，N-芊基-β-苯乙胺、去氫松香胺、N，N、 ^ 雙去氫-松香胺、葡萄糖胺、N-甲基葡萄糖胺，諸如峨淀、 柯林驗、奎寧或喹啉之吡啶型式之鹼，與諸如離胺酸與精 胺酸之鹼性胺基酸等形成之鹽。 這些鹽可由熟諳此藝者利用熟知之方法製備。 此外’因為對其接受者之潛在的溶劑毒性與因為溶劑功 能對藥物效力之改變；通常，並不需要調配含實質量之有 機溶劑（例如^乙酸乙酯）之醫藥。 “活性成分”之用語意指該化合物通常藉結構式I以及此~ 類化合物之鹽做說明。 醫樂可接受”之用語意指該載體、稀釋劑、賦形劑與鹽 必須與組合物之其他成份相容。本發明之醫藥組合物係利 用此藝熟知之方法藉熟知與易於取得之成分來製備。 “預防”係針對減少接受者產生或發展任何本文所述之病 情之可能。以該接受者經認為可能罹患該病情較佳。較佳〜 之接受者為類。 ， /口療係針對調停疾病或病情，並預防或減輕其進一步， 發展或改善與該疾病或病情相關之症狀。 醤栾有效I意指可誘發組織、系統或哺乳類之生物或 醫學反應之化合物或其鹽之量。可將此量預防性施用於經 認定易於發展疾病或病情之病人。當將其預防性施用於病 人時，此量亦可有效預防或減輕所調停的病情之嚴重性。 此量係欲包括足以調節PPARa受體或預防或調停疾病或病_ 85504.doc -24- 200406371 情：量：經讀《受體預防或治療之病情包括糖尿病、心 血$疾病、X症候群、肥胖症與腸胃病。 “哺乳類”為個別之分類上屬哺乳綱之動物1乳綱包括， 人類、猴子、黑獲獲、大獲獲、牛、豬、馬、绵羊、狗、 貓、小鼠與大鼠。 施用於人類最佳。本發明之化合物與組合物可用於治療 與/或預防心血管疾病，提高血清HDL膽固醇量、降低血清 ^甘油脂量並降低血班DL膽固醇量。高三甘油脂與^ — 量與低HDL,.係心臟病、中風與循環系統病症與疾病之危上· 險因子。〜 - 本發明 < 化合物與組合物亦可用於治療與/或預防肥胖 症。 甚且，這些化合物與組合物可用於治療與/或預防體重減 輕或體重未增加之非胰島素依賴型糖尿病（NIDDM)病患。 甚且，本發明之化合物與組合物可用於治療或預防諸如有 時會在手術一、創傷、心肌梗塞及其類似者後之胰島素敏感一 性之急性或|時性病症。一般醫生即可了解如何辨識因施 用本發明之化合物與組合物而受益之人。 - 本發明進一步提供治療與/或預防人類或非人之哺乳類 同血糖之方法’包括施予需要之高血糖的人或非人類之哺 乳類有效、無毒量之通式⑴化合物、或其互變異構型式與/ 或其醫藥可接受之鹽。 其可做為預防或治療人類或非人類之動物X症候群、糖尿 病與相關内分泌與心血管病症與疾病之治療藥劑之用。 Γ 85504.doc -25- 200406371 本發明亦係有關上述之式I化合物之製造治療PPAR α媒 介之病情的藥1勿之用途。salt. Such sounds are known as alkali addition salts, respectively. It should be understood that as long as the integrity of the salt is pharmaceutically acceptable, and as long as the counter ion does not contribute unnecessary properties to the salt as a whole, the characteristics of the specific counter ion forming part of any salt of the present invention are not important. Because of its acid portion, compounds of formula I will form salts with pharmaceutically acceptable bases. Examples of some test addition salts include metal salts such as sodium, potassium, sodium, potassium, and alkaline earth metal salts such as calcium and magnesium, and ammonium or substituted ammonium salts. Examples of substituted ammonium salts include, for example, those formed with lower alkyl amines such as trimethylamine, triethylamine, such as 2-hydroxyethylamine, bis- (2- 85504.doc -23- 200406371 hydroxyethyl) -Hydroxyalkylamines of amines or tri- (2-hydroxyethyl) -amines, such as dicyclohexylamine or dicyclohexylamine of dibenzylpiperidine, N-fluorenyl-β-phenylethylamine, dehydrorosin Amine, N, N, ^ dehydro-rosinamine, glucosamine, N-methylglucosamine, bases such as pyridine form of Edo, Colin test, quinine or quinoline, and bases such as lysine and quinoline Salts formed by basic amino acids of amino acids. These salts can be prepared by those skilled in the art using well-known methods. In addition, 'because of potential solvent toxicity to its recipients and because of changes in the effectiveness of the solvent function on the drug; usually, it is not necessary to formulate medicines containing solid organic solvents (such as ethyl acetate). The term "active ingredient" means that the compound is usually described by the formula I and the salts of such compounds. The term "medically acceptable" means that the carrier, diluent, excipient, and salt must be compatible with the other ingredients of the composition. The pharmaceutical composition of the present invention uses well-known and readily available ingredients using methods well known in the art. "Prevention" is aimed at reducing the possibility that a recipient may develop or develop any of the conditions described herein. It is better to consider that the recipient may be suffering from the condition. The recipients are better. To mediate a disease or condition, and prevent or reduce it further, develop or improve symptoms associated with the disease or condition. 醤 醤 effective I means the amount of a compound or its salt that can induce a biological or medical response in a tissue, system, or mammal This amount can be prophylactically administered to patients who are found to be prone to developing a disease or condition. When administered prophylactically to a patient, this amount is also effective in preventing or reducing the severity of the condition being mediated. This amount is intended to include Enough to regulate PPARa receptors or prevent or mediate diseases or illnesses _ 85504.doc -24- 200406371 Condition: Amount: After reading "Recipient prevention or treatment conditions include diabetes, heart blood Illness, Syndrome X, Obesity, and Gastrointestinal Diseases. "Mammals" are individual animals in the Mammalia category. Mammalia include: human, monkey, black, large, cattle, pig, horse, sheep, dog , Cat, mouse, and rat. Best for administration to humans. The compounds and compositions of the present invention can be used to treat and / or prevent cardiovascular diseases, increase serum HDL cholesterol, reduce serum glycerol, and lower blood DL Cholesterol amount. High triglyceride and ^ — amount and low HDL, are risk factors for heart disease, stroke and circulatory system disorders and diseases. ~-The present invention < compounds and compositions can also be used for treatment and / or Prevention of obesity. Furthermore, these compounds and compositions are useful in the treatment and / or prevention of non-insulin-dependent diabetes mellitus (NIDDM) patients who have lost or not gained weight. Furthermore, the compounds and compositions of the present invention are useful in the treatment of Or prevent acute or chronic conditions such as insulin sensitivity sometimes after surgery, trauma, myocardial infarction, and the like. General doctors can learn how to identify Benefited from the compounds and compositions of the invention.-The present invention further provides a method for the treatment and / or prevention of human or non-human mammals with blood glucose 'comprising administering an effective, non-toxic amount of human or non-human mammals with hyperglycemia in need. A compound of the general formula (I), or a tautomeric form thereof and / or a pharmaceutically acceptable salt thereof, which can be used as a therapeutic agent for the prevention or treatment of human or non-human animals with X syndrome, diabetes and related endocrine and cardiovascular disorders and diseases. Γ 85504.doc -25- 200406371 The present invention also relates to the use of the above-mentioned compound of formula I for the manufacture of a medicine 1 for the treatment of PPAR alpha-mediated diseases.

可用治療有效量之結構式I化合物製備用以治療下列疾 病之藥物：X症候群、糖尿病、治療肥胖症、降低三甘油脂 量、降低血清LDL量、提高血漿高密度脂蛋白之量，並治 療、預防或減輕動脈粥狀硬化發展之風險，並預防或減輕哺 乳類特別是人類之第一次或後續之動脈粥狀硬化疾病之風 險。通常，治療有效量乏本發明化合物典型地可降低病人 之血清三甘_濟脂量約20%或更多，而且，可增加病人之血清 HDL量。較佳蚤，HDL量可增加約30%或更多。此外，用以 預防或治療NIDDM之治療有效量之化合物典型地可降低病 人之血清葡萄糖，或更特定地HbAlc之量達約0.7%或更多。A therapeutically effective amount of a compound of structural formula I can be used to prepare a medicament for the treatment of the following diseases: syndrome X, diabetes, treatment of obesity, reduction of triglyceride lipids, reduction of serum LDL, increase of plasma high density lipoprotein, and treatment, Prevent or reduce the risk of atherosclerotic development, and prevent or reduce the risk of first or subsequent atherosclerotic diseases in mammals, especially humans. In general, a therapeutically effective amount of a compound of the present invention typically reduces the patient's serum triglyceride content by about 20% or more, and further increases the patient's serum HDL amount. More preferably, the amount of HDL can be increased by about 30% or more. In addition, a therapeutically effective amount of a compound used to prevent or treat NIDDM typically reduces the patient's serum glucose, or more specifically the amount of HbAlc, by about 0.7% or more.

有利地，含結構式I化合物或其鹽之組合物可採單位劑量 型式供應，較佳者係每個施用之劑量單位含由約1至約500 毫克，當然儘管很容易了解事實上施用之結構式I化合物之 量係由醫師_彦慮所有相關條件後決定。 當使用於本文時，X症候群包括前糖尿病之胰島素抗性症 候群及其造成之併發症、胰島素抗性、非胰島素依賴型糖 尿病、不良脂血症、高血糖症、肥胖症、凝血病變、高血 壓及其他與糖尿病相關之併發症。本文所提之方法與治療 包括上述者並涵蓋任一種下列或任何其合併者之治療與/ 或預防··前糖尿病之胰島素抗性症候群、其造成之併發症 、胰島素抗性、第二型或非胰島素依賴型糖尿病、不良脂 血症、高血糖症、肥胖症以及與包括心血管疾病尤其是動 85504.doc -26- 200406371 脈粥狀硬化之與糖尿病相關之併發症。 该組合物像以與本文詳述相同之一般方式調配並施用。 視所需之目標治療而定，本發明化合物可單獨，或合併一 或多種另外之活性成分有效地使用。合併療法包括施予單， 一之包含結構式I化合物與一或多種另外之活性成分之醫 藥劑量組合物，以及施予結構式;[化合物；與成為分開劑量 調配物之每種活性藥劑。例如，結構式〗化合物或其鹽類與 諸如縮二胍、嘧唑啶二酮、磺醯基尿素、胰島素或α•葡萄 糖苷酶抑制—f丨之胰島素促分泌劑，皆可利用諸如錠劑或膠‘鲁 囊之單一口服劑量組合物型式施予病人，或每個藥劑皆以 分開口服劑量調配物施予。當使用分開劑量調配物時，可 將結構式I化合物與一或多種另外之活性藥劑以實質上相 同時間，亦即同時或於岔開之時間，亦即依序施用；應了 解，合併療法包括所有這些療法。 動脈粥狀硬化之合併治療或預防之實例，可能為其中之 結構式I化t物或其鹽施用時，係合併一或多種下列之活性 成分：抗高血藤劑、血漿HDL_提昇劑、抗高血膽固醇劑、，· 苯氧芳酸、維生素、阿斯匹靈及其類似物。如上述，在施， 用結構式I化合物時可合併__或多種另外之活性成分。 另外-種合併療法之實例可在治療糖尿病與相關病症時 見之，其中該結構式I化合物、其鹽類可合併例如績驢基尿 素、縮二脈”塞切二鋼、α·葡萄糖料抑制劑、其他胰. 島素促分泌劑、胰島素以及上述討論之治療動脈粥狀硬化 之活性藥劑有效地利用。 85504.doc -27- 本發明化合物及其醫藥可接受之鹽，具有寶貴之藥理性 貝’而且’可~用於含治療有效量之本發明化合物或其醫藥 可接文 < 鹽，合併一或多種醫藥可接受賦形劑之醫藥組合 物。賦形劑係諸如非限制性之載體、稀釋劑、填充劑、調 味劑、甜味劑、潤滑劑、溶解劑、懸浮劑、濕潤劑、接著 劑、分解劑、包覆材料及其他慣用佐劑之惰性物質。適當 調配物視所選之施用路徑而定。醫藥組合物典型地包含由 約1至約99重量百分比芝本發明化合物之活性成分。 車又佳者，多醫藥碉配物係為單位劑量型式。，，單位劑量型 式為適於施與人類病患或其他哺乳類之含單位劑量之物 理不連續里。例如，單位劑量型式可以為膠囊或錠劑，或 一些膠囊或錠劑。“單位劑量，，為預先決定量之經計算以產 生所而治纟效果之本發明之活性化合物，冑合一或多種醫 藥可接文心賦形劑。根據所涉之特別治療而定，該單位劑 里惑活性成分的量可以不同，或由約〇1至約1〇〇〇毫克或更 多做调整。 該使用本i明化合物之劑量療法係由一般熟諳醫學或獸 醫技藝者、考慮不同因素，包括非限制性之物種、年齡、 體重、性別與接受者之醫療條件、所治療病情之嚴重性、 施用路;^、接x者之代謝程度與分泌功能、所用之劑量型 式、所用之特定化合物及其鹽’及其類似物。 較佳者，本發明化合物係以單一日劑量施用或可將總日 劑量分成每天2、3或更多次劑量施用。當然，在經皮型式 傳送時，施用係連續的。 85504.doc -28- 200406371 施用本發明之醫藥組合物之適當路徑包括，例如口、眼 藥、直腸、愈—黏膜、局部或小腸施用，非經腸傳送（巨丸或 浸潤），包括肌内、皮下、脊髓内注射、以及椎管内、直接 腦室内、靜脈内、腹膜内、鼻内、或眼内注射。本發明化 · 合物可採其例諸如塗覆内皮細胞專一性抗體之脂質體之目 標藥物傳送系統施用。 對於口服施用者，可將該活性成分與此藝熟知之醫藥可 接义載體合併而很方便地調配該化合物。此類載體使得本 一 發明化合物〜可調配成錠劑、藥丸、粉末、香包、顆粒、糖 j 衣藥丸、膠囊'液體、萬能藥、酊劑、膠、乳液、糖漿、 泥永懸浮液及其類似物，以供接受治療之病人口服攝入 。欲取得供口服之醫藥製備物，可藉合併活性化合物與固 體賦形劑，並於添加適當輔助劑後，於必要時，視情形研 磨生成之混合物，並加工該顆粒之混合物，以取得錠劑或 糖衣藥丸核心。 對口服施^之錠劑或膠囊型式者，可將該活性成分與口 _ 服、無毒性之醫藥可接受載體合併，諸如非限制性之乳糖’ 蠃勃蔗糖、葡萄糖、甲基纖維素、碳酸鈣、磷酸鈣、 、碳酸納、甘露醇、山梨醇及類似物；視情形加上 :解劑’諸如非限制性之交聯聚乙晞料淀酮、玉米、澱 表甲基纖維素、瓊脂、膨潤土、三仙膠、藻膠酸、或其. 逢如永酸制之鹽、及其類似物；與視情形加上結合劑，例 4非限制性之明膠、阿拉伯樹膠、天然糖、卜乳糖、玉米 甘未训天然與合成膠、黃蓍膠、藻酸鈉、羧甲基纖維素- 85504.doc -29- 200406371 、聚乙二醇、蠟及其類似；與視情形之潤滑劑，例如非限 制性之硬脂鎂、硬脂酸鈉、硬脂酸、油酸鎂、芊酸鈉、 乙酸鈉、氯化鈉、滑石及其類似物。當單位劑量型式為膠 囊時，除了上述型態之材料外，其可包含諸如脂肪油之液 體載體。 / 固體型式調配物包括粉末、錠劑與膠囊。固體載體可為 一或多種亦可做為調味劑、潤滑劑、溶解劑、懸浮劑、接 著劑、鍵劑分解劑與包覆材料之物質。 就粉末者〜^該載體為混合精細區分之活性成分之精細區 分之固體。就》走劑者，該活性成分係以適當比例混合具必 要結合性質之載體，並壓縮成所需型態與大小。 亦可存在當作塗覆物或修飾劑量單位之物理型式之不同 的其他材料。例如，可將錠劑塗覆虫膠、糖或二者。除了 活性成分之外，糖漿或萬能藥可以包含做為甜味劑之蔑糖 、做為防腐劑之苄酸甲與丙酯、染料與諸如櫻桃或甜橘味 道之調味料。 無菌之液體調配物包括懸浮液、乳液、糖漿與萬能藥。可 將該活性成分溶解或懸浮於諸如無菌水、無菌有機溶劑或 無菌水與無菌有機溶劑二者之混合物之醫藥可接受載體。 亦可將該活性成分溶解於例如水性丙二醇之適當有機溶 劑。可藉將該精細區分之活性成分懸浮於水性澱粉或叛甲 基纖維素鈉溶液或適當之油製成其他組合物。 糖衣藥丸核心係以適當塗覆物供應。為此目的，可使用 濃縮之糖溶液，其可視情形包含阿拉伯膠、滑石、聚乙晞 85504.doc -30- 200406371 吡咯啶酮、卡柏波（carbopol)膠、聚乙二醇與/或二氧化鈦、 塗漆溶液與迹'當之有機溶劑或溶劑混合物。為辨識或定活 = 性化合物劑量之不同組合，亦可將染料或色素加至錠劑或 糖衣藥丸塗覆物。 - 可供口服施用之醫藥製備物包括，由明膠製成之密封 (push-fit)膠囊，以及由明膠與諸如甘油或山梨醇之塑型劑 製成之軟的、封口膠囊。該密封膠囊可包含混合諸如乳糖 之填充劑、諸如殿粉之接著劑、與/或諸如滑石或硬脂酸鍰 — 之潤滑劑，喪視情形加上安定劑之活性成分。在阮膠囊情 3· 一· — * 形，可將該活性成分溶解或懸浮於諸如脂肪油、液體石犧 、或液體聚乙二醇之適當液體。此外，可添加安定劑。 所有供口服施用之調配物皆應為適於此施用之劑量。特 別適合供口服施用之組合物為諸如錠劑與膠囊之單位劑量 型式。 對於非經腸施用者，可將本發明化合物或其鹽合併無菌 之水性或有機媒介，以形成注射用溶液或懸浮液。供注射 — 用之調配物3Γ採諸如利用安瓶，或多劑量容器之單位劑量，籲 型式並添加防腐劑呈現。該組合物可為諸如懸浮液、溶液 一 或利用油性或水性載體之乳液之型式，並可包含諸如懸浮 用、安定用與/或分散用之藥劑之調配劑。適於注射用之醫 藥型式包括，無菌水性溶液或分散液，與供即時性製備無 菌注射溶液或分散液之無菌粉末。在所有情形，該型式必 。 須為無菌且必須為存在個別之注射性之流體程度。其在製 造與貯存條下必須是安定的，且必須防止任何污染。該載 ^ 體可為包含例如水之溶劑或分散媒介，較佳者係諸如漢克 ~ 85504.doc -31- 200406371 溶液、林格氏液，或生理食鹽緩衝液、乙醇、多醇（例如甘 油、丙二醇輿一液體聚乙二醇）、其適當混合物與蔬菜油之具 生理相容性之緩衝液。在普通貯存與使用條件下，這些製 備物包含預防微生物生長之防腐劑。 以此方式製備之注射用溶液，可採靜脈内、腹膜内、皮 下或肌内施用，對人類者以肌内施用較佳。 對經黏膜施用時，在調配物中使用適於穿透障礙之穿透 劑。此類穿透劑係此藝'所周知者。該活性化合物亦可採例 如液體滴劑或噴劑型式鼻内施用。 對於頰施"'用特，該組合物可為採慣用方式調配之錠劑或 糖錠型式。 >對於吸入施用時，根據本發明所用之化合物可很方便地 採乾粉吸入劑，或由加壓包裝或雲狀劑呈現之氣融膠噴霧 土式’並使用例如二氟二氯甲燒、三氯氟甲燒、四氣二氯 乙烷、一虱化碳或其他適當氣體之適當推進劑傳送。在加 逢融膠^ 可藉提供—個傳送測定量之閥以決定該 剡里單位劑或充氣機所用之膠囊與明膠盒子，可調 配成包含本化合物與諸如乳糖或殿粉之適當粉末基質之粉 末混合物。 n 本發明之醫藥组合物可採本身熟知之方式 用慣用之混合、溶觝π b w如才' ’成顆粒、製糖衣藥丸、磨細、到 化、包覆、包裹每、卷 令凍乾燥等方法。 在製造本發明組人4 、、且口物時，通常會將該活性成分與載體渴 合，或經載體稀釋，七〜入 、戰缸似 、紙張或其他容器刑+ ^ 畏胥己 &土式。當該載體係做為稀釋劑時，立石Advantageously, the composition containing the compound of Formula I or a salt thereof may be supplied in a unit dosage form, preferably from about 1 to about 500 mg per dosage unit administered, although of course it is easy to understand the structure in fact The amount of the compound of formula I is determined by the physician_yan after considering all relevant conditions. As used herein, Syndrome X includes pre-diabetic insulin resistance syndrome and its complications, insulin resistance, non-insulin-dependent diabetes mellitus, dyslipidemia, hyperglycemia, obesity, coagulopathy, hypertension And other complications related to diabetes. The methods and treatments mentioned herein include the above and cover the treatment and / or prevention of any of the following or any combination thereof: pre-diabetic insulin resistance syndrome, its complications, insulin resistance, type 2 or Non-insulin-dependent diabetes mellitus, dyslipidemia, hyperglycemia, obesity, and diabetes-related complications including atherosclerosis, including cardiovascular disease, especially 85504.doc -26- 200406371. The composition is formulated and applied in the same general manner as detailed herein. Depending on the desired target treatment, the compounds of the invention can be effectively used alone or in combination with one or more additional active ingredients. Concomitant therapies include a single administration sheet, a medicinal dosage composition comprising a compound of formula I and one or more additional active ingredients, and administration of a structural formula; [compound; and each active agent as a separate dosage formulation. For example, compounds of the formula or their salts with insulin secretagogues such as biguanide, pyrazolidinedione, sulfonylurea, insulin, or α-glucosidase inhibitor-f, can be used such as lozenges Or a single oral dosage composition of the gelatin capsule is administered to the patient, or each agent is administered as a separate oral dosage formulation. When using separate dosage formulations, the compound of formula I and one or more additional active agents may be administered at substantially the same time, i.e., simultaneously or at separate times, i.e., sequentially; it should be understood that combined therapy includes All these therapies. An example of combined treatment or prevention of atherosclerosis may be the structural formula I or a salt thereof, which is combined with one or more of the following active ingredients: anti-hypertensive agent, plasma HDL_ booster, Anti-hypercholesterol, phenoxy aromatic acid, vitamins, aspirin and the like. As described above, when applying the compound of formula I, one or more additional active ingredients may be combined. In addition, an example of a combination therapy can be seen in the treatment of diabetes and related disorders, in which the compound of structural formula I and its salts can be combined, for example, chitin-based urea, bismuth, "Secceta II steel, α-glucose inhibitor Agents, other pancreas. Insulin secretagogues, insulin, and active agents for treating atherosclerosis discussed above are effectively used. 85504.doc -27- The compounds of the present invention and their pharmaceutically acceptable salts have valuable pharmacology Shellfish can also be used in a pharmaceutical composition containing a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients. Excipients such as non-limiting Carriers, diluents, fillers, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, wetting agents, adhesives, disintegrating agents, coating materials and other inert substances commonly used as adjuvants. Appropriate formulation depends on the place The route of administration depends on the choice. The pharmaceutical composition typically contains from about 1 to about 99% by weight of the active ingredient of the compound of the present invention. In a preferred embodiment, the multi-medicine formulation is a unit dosage form. A unit dose pattern is a physical discontinuity containing a unit dose suitable for administration to human patients or other mammals. For example, a unit dose pattern can be a capsule or lozenge, or some capsules or lozenges. "Unit dose, , Is a predetermined amount of the active compound of the present invention which is calculated to produce the desired curative effect, and is combined with one or more pharmaceutically acceptable excipients. Depending on the particular treatment involved, the amount of active ingredient in the unit dose may vary or be adjusted from about 0.001 to about 10,000 mg or more. The dosage therapy using the compound of the present invention is generally understood by a person skilled in medicine or veterinary medicine, taking into account different factors, including non-limiting species, age, weight, sex and the medical conditions of the recipient, the severity of the condition being treated, administration Road; ^, the degree of metabolism and secretory function of the person receiving x, the dosage form used, the specific compound used and its salt 'and its analogs. Preferably, the compounds of the invention are administered in a single daily dose or the total daily dosage may be divided into two, three or more daily doses. Of course, during transdermal delivery, the application is continuous. 85504.doc -28- 200406371 Appropriate routes for administering the pharmaceutical compositions of the present invention include, for example, oral, ophthalmic, rectal, muco-mucosal, topical or small intestine administration, parenteral delivery (giant pill or infiltration), including intramuscular , Subcutaneous, intraspinal, and intraspinal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injection. The compounds of the present invention can be administered by targeting drug delivery systems such as liposomes coated with endothelial cell specific antibodies. For oral administration, the compound can be conveniently formulated by combining the active ingredient with a pharmaceutical acceptable carrier known in the art. Such carriers enable the compounds of the present invention to be formulated into lozenges, pills, powders, sachets, granules, sugar j-coated pills, capsules' liquids, panaceas, tinctures, gums, emulsions, syrups, mud suspensions and Analogs for oral ingestion by a treated patient. To obtain a pharmaceutical preparation for oral administration, the active compound and solid excipients can be combined, and after adding an appropriate adjuvant, if necessary, the resulting mixture is ground as appropriate, and the mixture of particles is processed to obtain a tablet Or sugar-coated pills core. For oral administration in the form of tablets or capsules, the active ingredient can be combined with an oral, non-toxic pharmaceutically acceptable carrier such as non-limiting lactose, sucrose, glucose, methyl cellulose, carbonic acid Calcium, calcium phosphate, sodium carbonate, mannitol, sorbitol, and the like; plus: as appropriate, an antidote 'such as a non-limiting cross-linked polyethylene glycol, ketones, corn methyl cellulose, agar , Bentonite, sanxian gum, alginic acid, or its salts, and the like made from peracid; and adding a binding agent as appropriate, Example 4 Non-limiting gelatin, gum arabic, natural sugar, Bu Lactose, corn glutamate natural and synthetic gum, tragacanth gum, sodium alginate, carboxymethylcellulose-85504.doc -29- 200406371, polyethylene glycol, wax and similar; lubricants as appropriate, For example, non-limiting magnesium stearate, sodium stearate, stearic acid, magnesium oleate, sodium gallate, sodium acetate, sodium chloride, talc and the like. When the unit dosage form is a capsule, it may contain a liquid carrier such as a fatty oil in addition to the above-mentioned materials. / Solid form formulations include powders, lozenges and capsules. The solid carrier can be one or more substances which can also be used as flavoring agents, lubricants, dissolving agents, suspending agents, binding agents, bond disintegrating agents and coating materials. For powders, the carrier is a finely divided solid that mixes finely divided active ingredients. For those who take the agent, the active ingredient is mixed with the carrier with the necessary binding properties in an appropriate ratio and compressed into the desired shape and size. There may also be other materials that differ in physical form as coatings or modified dosage units. For example, lozenges can be coated with shellac, sugar or both. In addition to the active ingredients, syrup or a panacea may contain sugar as a sweetener, methyl and propyl benzate as a preservative, dyes and seasonings such as cherry or sweet orange flavor. Sterile liquid formulations include suspensions, emulsions, syrups and panaceas. The active ingredient may be dissolved or suspended in a pharmaceutically acceptable carrier such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent. This active ingredient may also be dissolved in a suitable organic solvent such as aqueous propylene glycol. Other compositions can be made by suspending this finely divided active ingredient in aqueous starch or sodium methylcellulose solution or a suitable oil. The core of the sugar-coated pills is supplied in a suitable coating. For this purpose, a concentrated sugar solution may be used, which may include gum arabic, talc, polyethylene fluorescein 85504.doc -30- 200406371, as appropriate, pyrrolidone, carbopol gum, polyethylene glycol, and / or titanium dioxide The paint solution and traces should be treated as organic solvents or solvent mixtures. Dyes or pigments can also be added to lozenges or sugar-coated pill coatings to identify or animate different combinations of active compound doses. -Pharmaceutical preparations for oral administration include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a molding agent such as glycerin or sorbitol. The sealed capsule may contain an active ingredient such as a filler such as lactose, an adhesive such as gluten powder, and / or a lubricant such as talc or rhenium stearate, in the case of blindness plus a stabilizer. In the shape of Ruan Capsule 3 ···, the active ingredient can be dissolved or suspended in a suitable liquid such as fatty oil, liquid stone, or liquid polyethylene glycol. In addition, stabilizers can be added. All formulations for oral administration should be in a dosage suitable for such administration. Compositions particularly suitable for oral administration are unit dosage forms such as lozenges and capsules. For parenteral administration, the compound of the present invention or a salt thereof can be combined with a sterile aqueous or organic vehicle to form a solution or suspension for injection. For injection — The formulation 3Γ is taken in unit doses such as in ampoules or multi-dose containers, and is presented in the form of preservatives. The composition may be in the form of, for example, a suspension, a solution, or an emulsion using an oily or aqueous carrier, and may include a formulation such as a suspending, stabilizing, and / or dispersing agent. The types of medicines suitable for injection include sterile aqueous solutions or dispersions, and sterile powders for the immediate preparation of sterile injection solutions or dispersions. In all cases, this type must. It must be sterile and must have a degree of individual injectable fluid. It must be stable under manufacturing and storage strips and must be protected from any contamination. The carrier may be a solvent or dispersion medium containing, for example, water, and is preferably a solution such as Hank ~ 85504.doc -31- 200406371, Ringer's solution, or a physiological salt buffer solution, ethanol, a polyol (such as glycerin , Propylene glycol (a liquid polyethylene glycol), a physiologically compatible buffer solution of its proper mixture with vegetable oil. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The injection solution prepared in this way can be administered intravenously, intraperitoneally, subcutaneously or intramuscularly, and is preferably administered intramuscularly to a human. For transmucosal application, penetrants suitable for penetrating barriers are used in the formulation. Such penetrants are well known in the art. The active compound may also be administered intranasally, for example, as a liquid drop or spray. For buccal application, the composition may be in the form of lozenges or lozenges formulated in a conventional manner. > For inhalation administration, the compound used according to the present invention can be conveniently taken as a dry powder inhaler, or an aerosol gel spray earth type presented by a pressurized package or clouding agent, and using, for example, difluorodichloromethane, Trichlorofluoromethane, tetragas dichloroethane, carbon monoxide, or other appropriate gas propellant. In addition, a plastic valve can be provided to determine the capsules and gelatin boxes used for the unit dose or the inflator, which can be formulated to contain the compound and an appropriate powder base such as lactose or gluten. Powder mixture. n The pharmaceutical composition of the present invention can be mixed and dissolved in a conventionally well-known manner, using conventional methods such as bw, granulation, sugar-coated pills, grinding, chemical conversion, coating, wrapping, freeze-drying, etc. method. When manufacturing the group 4 of the present invention, and the mouthpiece, the active ingredient is usually combined with the carrier, or diluted with the carrier, seven to enter, war tank-like, paper or other container punishment + 胥 胥 己 & Earthly. When the carrier is used as a diluent,

S5504.doc -32- 200406371 2固體、冷綠_體或糊狀、半固體、或做為載體之液 =材料；或^含例如達1G重量％之活性成分之錠劑、藥丸、 知末、糖錠、萬能藥、縣淬汸 日^、 朱心，予履、礼欣、溶液、糖漿、氣溶S5504.doc -32- 200406371 2 solid, cold green body or paste, semi-solid, or liquid as a carrier = material; or ^ tablets, pills, zhimo, containing active ingredients such as up to 1G% by weight, Sugar lozenges, panacea, county quenching day ^, Zhu Xin, Yu Lu, Li Xin, solution, syrup, air soluble

勝（為固體或溶於液體媒介、、士 I 把踩；丨由霄型式。本發明化合物在施 用前先調製較佳。 、下列醫藥調配物1與2⑽供說明用S，無論如何皆非用 以限制本發明料。“活性成分，，料對根據結構式丨之化合 物或其鹽。 調配物1 硬明膠膠―囊係利用下列成分製成：Sheng (is a solid or dissolved in a liquid medium, and I step on; from the Xiao type. The compound of the present invention is better prepared before administration.) The following pharmaceutical formulations 1 and 2 are for illustration S, but are not used in any way. In order to limit the material of the present invention. "The active ingredient, the compound is a compound according to the structural formula or its salt. Formulation 1 Hard gelatin-The capsule system is made with the following ingredients:

活性成分 乾澱粉 硬脂酸鎂 總量 (臺克/膠嚢） 250 200 10. 460毫克 調配物2 鍵劑係利用下列成分製成： 量 (亳克/錠劑） 250 400 10 5 665毫克 活性成分 微結晶纖維素 薰過之二氧化矽 硬脂酸 總量 85504.doc 33 200406371 將成份混合並壓縮形成每個重665毫克之錠劑。 在本發明紐τ合物之又一個具體實施例，我們利用諸如碳 -14或氚化將該化合物放射標定。該放射標定或氚化之化合 物可做為辨識新的PPARa及或ppAR§激動劑之活體外分析 之參考標準用。 合成 本發明化合物係如特定之在實例所說明般製成。甚且， 很多化合物係根據下列圖式所示之更通常方法製備者。替 代之合成方〜法亦可能有效，而且係熟諳此藝者所熟知。 ' 圖式1 醯胺產物合成之一般實驗方法 製備物1Active ingredients Total dry starch magnesium stearate (Tec / Capsules) 250 200 10. 460 mg Formulation 2 The bonding agent is made with the following ingredients: Amount (Tec / Lozenges) 250 400 10 5 665 mg Active Ingredients Total amount of microcrystalline cellulose fumed silica stearic acid 85504.doc 33 200406371 The ingredients are mixed and compressed to form tablets each weighing 665 mg. In yet another specific embodiment of the neotau compound of the present invention, we radiocalibrate the compound using, for example, carbon-14 or tritiated. This radiometric or tritiated compound can be used as a reference standard for in vitro analysis to identify new PPARa and or ppAR§ agonists. Synthesis The compounds of the present invention are prepared as specifically illustrated in the examples. Moreover, many compounds are prepared according to the more general method shown in the following scheme. Alternative methods of synthesis may also be effective and well known to those skilled in the art. '' Scheme 1 General experimental method for the synthesis of amidine products Preparation 1

CH3CH3

ch3 步騾1 3-溴-丙_1_醇 將1，3_丙二醇（10.26克、134·8毫莫耳）溶於苯（150毫升）。 將HBr 48% (16.84毫升）加入此溶液，然後於共沸去除水條 件下迴流24小時。於大氣壓下蒸發溶劑。以乙醚（15〇毫升） 稀釋殘渣並經水（3 X 50毫升）洗。令有機層經MgS04脫水並 濃縮以提供黃色油。iH-NMR (CDC13, 200.15 MHz) : 3.80 (t 2H，J=6.4)，3·54 (t，2H，J=6.5)，2.10 (qn，2H，J=6.4)。 85504.doc -34- 200406371 步騾2 (2S)-3-[4-(3·^-丙氧基）_苯基]-2-甲氧基-丙酸乙酯 沒 令三苯膦（4.77毫莫耳、1250毫克）之50毫升無水甲苯溶液 ' 於0°C經偶氮二羧酸二異丙酯（4.77毫莫耳、964.5毫克）處理 -並攪拌20分鐘。將（2S)-3_(4-羥基-苯基）-2-甲氧基-丙酸乙酯 (實例1、步驟1)(4.46毫莫耳、1000毫克）與3-溴丙-1-醇（實 例2、步騾1)(4.77毫莫耳、663毫克）之10毫升無水THF溶液 加至該溶液’並令該混合物於室溫隔夜擾摔。令該混合物 〜 於真空中濃〜维至乾，並經矽膠層析（矽膠、己烷/乙酸乙酿6 :1)純化。將;ίϋ當於偶合化合物之具Rf 〇·4之部分合併，迷 濃縮至乾以提供黃色油。C15H21Br04 [M+Na]+之MS (ES): 367.2 〇 製備物2 步騾1ch3 Step 1-3-bromo-propan-1-ol Dissolve 1,3-propanediol (10.26 g, 134.8 mmol) in benzene (150 ml). HBr 48% (16.84 ml) was added to this solution, and then refluxed for 24 hours under azeotropic removal of water. The solvent was evaporated at atmospheric pressure. The residue was diluted with ether (150 ml) and washed with water (3 x 50 ml). The organic layer was dehydrated with MgS04 and concentrated to provide a yellow oil. iH-NMR (CDC13, 200.15 MHz): 3.80 (t 2H, J = 6.4), 3.54 (t, 2H, J = 6.5), 2.10 (qn, 2H, J = 6.4). 85504.doc -34- 200406371 step 2 (2S) -3- [4- (3 · ^ -propoxy) _phenyl] -2-methoxy-propionic acid ethyl ester triphenylphosphine (4.77 50 ml of anhydrous toluene solution in millimoles, 1250 mg) was treated with diisopropyl azodicarboxylate (4.77 millimoles, 964.5 mg) at 0 ° C-and stirred for 20 minutes. (2S) -3_ (4-hydroxy-phenyl) -2-methoxy-propionic acid ethyl ester (Example 1, step 1) (4.46 mmol, 1000 mg) and 3-bromopropan-1-ol (Example 2, step 1) (4.77 mmol, 663 mg) of 10 ml of anhydrous THF solution was added to the solution 'and the mixture was allowed to stir overnight at room temperature. The mixture was concentrated to dryness under vacuum and purified by silica gel chromatography (silica gel, hexane / ethyl acetate 6: 1). The R? Of the coupling compound was combined with Rf 0.4, and concentrated to dryness to provide a yellow oil. C15H21Br04 [M + Na] + MS (ES): 367.2 〇 Preparation 2 Step 1

3-(4-爷氧基·苯基）-2-乙氧基-3·#呈基-丙酸乙酉旨 標題化合物係經由用以製備3-(3-芊氧基-苯基）-3-羥基-2-甲氧基-丙酸甲酯（實例9、步驟1)之相同方法由4-芊氧基苄 醛、二異丙醯胺化鋰與2-乙氧基乙酸乙酯製成。C2〇H24〇5 [M+H20-H] +之 MS (ES) : 327, [M+Na]+ : 367.4。 步騾23- (4-Ethoxy-phenyl) -2-ethoxy-3 · # presenting group-acetic acid propionate The title compound was prepared by using 3- (3-methoxy-phenyl) -3 -Hydroxy-2-methoxy-propionic acid methyl ester (Example 9, step 1) was prepared from 4-methoxybenzaldehyde, lithium diisopropylamidide and ethyl 2-ethoxyacetate . MS (ES) for C20H24〇5 [M + H20-H] +: 327, [M + Na] +: 367.4. Step 2

85504.doc -35- 200406371 3-(4-爷氧基-苯基）-2-乙氧基-丙埽酸乙酉旨 標題化合物^係經由用以製備3-(4-芊氧基·苯基）-2-乙氧基 -丙埽酸甲酯之相同方法由3-(4-苄氧基-苯基）-2-乙氧基-3-幾基-丙酸乙酯（實例93、步驟1)製成。C2〇H2204 [M+H] +之 MS(ES) ·· 327.2。 步騾385504.doc -35- 200406371 3- (4-Ethoxy-phenyl) -2-ethoxy-propionate ethyl acetate The title compound ^ is used to prepare 3- (4-fluorenyloxyphenyl) ) -2-Ethoxy-propionate methyl ester The same method was used 3- (4-benzyloxy-phenyl) -2-ethoxy-3-quinyl-propionic acid ethyl ester (Example 93, step 1) Made. MS (ES) for C20H2204 [M + H] + 327.2. Step 3

3 _(4-芊氧卷-笨基）_1•乙氧基-丙酸甲酯 標題化合物係經由用以製備3-(3-苄氧基-苯基）-2-甲氧基 -丙酸甲酯（實例9、步驟3)之相同方法由3-(4-苄氧基-苯基） -2-乙氧基-丙烯酸乙酯（實例93、步驟2)(3.3克、10.12毫莫耳） 所製備，以生產經層析（矽膠、己烷/乙酸乙酯6 : 〇純化之 油以生產兩種化合物：3_(4-苄氧基_苯基）_丙酸甲酯（丨·5克3 _ (4-fluorenyl-benzyl) _1 • ethoxy-propionic acid methyl ester The title compound was prepared via the preparation of 3- (3-benzyloxy-phenyl) -2-methoxy-propionic acid The same method for methyl ester (Example 9, Step 3) was performed from 3- (4-benzyloxy-phenyl) -2-ethoxy-ethyl acrylate (Example 93, Step 2) (3.3 g, 10.12 mmol) ) Prepared to produce an oil purified by chromatography (silica gel, hexane / ethyl acetate 6: 〇 to produce two compounds: 3_ (4-benzyloxy_phenyl) _methyl propionate (丨 · 5 Gram

Rf約0.65)與所需化合物（1.5 克 Rf 約〇.2)。C19H22〇4 [Μ+ΝΗ4] + 之 MS(ES) ··飞32.3。 步騾4Rf of about 0.65) and the desired compound (1.5 g of Rf of about 0.2). MS (ES) for C19H22〇4 [M + ΝΗ4] + · 32.3. Step 4

85504.doc • 36 - 1 -乙氧基- 3- (4-經基基）_丙酸甲酉旨 才衣通化合物係經由用以製備3 - (3 -經基-苯基）_ 2 -甲氧基_ 丙酸甲酯（實例9、步騾4)之相同方法由3_(4_苄氧基_苯基）_2_ 200406371 乙氧基-丙酸甲酯（實例93、步驟3)製備，以生產黃色油 CuHbCMM+kl ㈣：225·2, [m+NH4]+ ·· 242·2, [M+Na]+ :247.2。 製備物3 (2S)-2-甲氧基-3-(4]2-氧基_2_[4_(4_三氟甲基-苯基）.井 ―1-基]-乙氧基卜苯基）_丙酸 $ . %，對掌體85504.doc • 36-1 -Ethoxy-3-(4-Cycyl) _formamidine propionate is only used to prepare 3-(3 -Cyclo-phenyl) _ 2- The same method of methoxy_methyl propionate (Example 9, step 4) was prepared from 3_ (4_benzyloxy_phenyl) _2_ 200406371 ethoxy-propionic acid methyl ester (Example 93, step 3), To produce yellow oil CuHbCMM + kl ㈣: 225 · 2, [m + NH4] + ·· 242 · 2, [M + Na] +: 247.2. Preparation 3 (2S) -2-methoxy-3- (4) 2-oxy_2_ [4_ (4_trifluoromethyl-phenyl). Well-1-yl] -ethoxybenzene Base) _ Propionate $.% On palm body

步騾1 : (2S)-3-(4•第三·丁氧羰甲氧基-苯基）_孓甲氧基-丙酸 乙酯Step 骡 1: (2S) -3- (4 · Third · Butoxycarbonylmethoxy-phenyl) _ 孓 methoxy-propionic acid ethyl ester

令化合竣一(2S)-3-(4-羥基-苯基）-2-甲氧基-丙酸酯（實例1 、步驟1)(1.2克、5.3毫莫耳）溶於25毫升無水THF，並分次 加入NaH(380毫克、15·8毫莫耳）。約5分鐘後，於室溫下逐 滴添加溴乙酸第三-丁酯。令混合物於室溫攪拌2小時。溶 粗產物於乙酸乙酯（1〇〇毫升），並添加5% HC1溶液。令該混 合物經乙酸乙酯萃取（3 X 100毫升），並令合併之有機層經 MgSCU脫水，然後真空濃縮。令粗產物經管柱層析（硬膠、 己烷/乙酸乙酯8.5 : 1.5)純化，以提供黃色油。 步驟2 : (2 S)-3 - (4-棱甲氧基-苯基）-2 -甲乳基-丙酸乙酉旨 85504.doc -37- 200406371 y^〇(2S) -3- (4-hydroxy-phenyl) -2-methoxy-propionate (Example 1, Step 1) (1.2 g, 5.3 mmol) was dissolved in 25 ml of anhydrous THF And add NaH (380 mg, 15.8 mmol) in portions. After about 5 minutes, tert-butyl bromoacetate was added dropwise at room temperature. The mixture was allowed to stir at room temperature for 2 hours. The crude product was dissolved in ethyl acetate (100 mL) and a 5% HC1 solution was added. The mixture was extracted with ethyl acetate (3 X 100 ml), and the combined organic layers were dehydrated with MgSCU and concentrated in vacuo. The crude product was purified by column chromatography (hard gum, hexane / ethyl acetate 8.5: 1.5) to provide a yellow oil. Step 2: (2 S) -3-(4-Edgemethoxy-phenyl) -2-methyllactyl-acetic acid propionate 85504.doc -37- 200406371 y ^ 〇

令化合物（2S)-3-(4-第三-丁氧羰甲氧基-苯基）-2-f氧基_ 丙酸乙酯（製備物3、步驟1)(1.2克、3.5毫莫耳）溶於二氯甲 烷（5毫升），並添加三氟乙酸（5毫升）。令該混合物攪拌^】、 時’並濃縮粗產物以提供黃色油。iH-NMr (CDC13，200 15 MHz) : 7.16 (d，2H，J=8』），6.75 (d，2H，J=8.3)，4·89 (s, 2H)， 4·14 (c，2Η^Γ=6·9)，3.94 (t，1H，J=6.9)，3.57 (dc，1H)，3·35 3籲 (dc，1H)，2:92 (d，2H，J=6.9)，1·23-1·1〇 (2t，6H)。 步驟3 : (2S)_2_甲氧基-3-(4_{2_氧基_2-[4-(4-三氟甲基_苯基） •哌畊-1·基]-乙氧基}•苯基）_丙酸Let compound (2S) -3- (4-Third-butoxycarbonylmethoxy-phenyl) -2-foxy_ ethyl propionate (Preparation 3, Step 1) (1.2 g, 3.5 mmol) Ear) was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (5 ml) was added. The mixture was allowed to stir for 15 hours, and the crude product was concentrated to provide a yellow oil. iH-NMr (CDC13, 200 15 MHz): 7.16 (d, 2H, J = 8 ′), 6.75 (d, 2H, J = 8.3), 4.89 (s, 2H), 4.14 (c, 2Η ^ Γ = 6.9), 3.94 (t, 1H, J = 6.9), 3.57 (dc, 1H), 3.35 3 (dc, 1H), 2:92 (d, 2H, J = 6.9), 1.23-1.10 (2t, 6H). Step 3: (2S) _2_methoxy-3- (4_ {2_oxy_2- [4- (4-trifluoromethyl_phenyl) • piperin-1 · yl] -ethoxy } • phenyl) _propionic acid

標題化合係經由用以製備（2S，乙氧基_3_(4_〇_ [2-(4-苯氧基-苯基）_乙基胺甲醯基]_乙氧基卜苯基丙酸（實 例1、步驟3)之相同方法由（28)_3-(4_叛甲氧基·苯基）_2_甲氧 基-丙酸乙酯（製備物3、步驟2)與1-(4_三氟甲基_苯基哌畊 製備’以生產無色油。C23H25F3N〇5 [M+h]+之MS (ES) : 467。 fwf對掌體 製備物4 (3_{[2-(4-乙基-苯基）_乙基胺甲醯基卜甲氧基卜苯基）_2_甲 氧基-丙酸（異構物1) 85504.doc -38- 200406371The title compound is used to prepare (2S, ethoxy_3_ (4_〇_ [2- (4-phenoxy-phenyl) _ethylaminemethyl)] _ ethoxyphenylphenylpropanoic acid (Example 1, step 3) The same method was used (28) _3- (4_metamethoxy · phenyl) _2_methoxy-propionic acid ethyl ester (preparation 3, step 2) and 1- (4 _Trifluoromethyl_phenylpiperin preparation 'to produce a colorless oil. MS (ES) of C23H25F3NO5 [M + h] +: 467. fwf palm preparation 4 (3 _ {[2- (4- Ethyl-phenyl) _Ethylaminomethylmethylphenylmethoxyphenyl) _2_methoxy-propionic acid (Isomer 1) 85504.doc -38- 200406371

_苯基）_2-甲氧基-丙酸甲酯 步騾1 : 3_(3-第三·丁氧羰甲氧基_Phenyl) _2-methoxy-propionic acid methyl ester Step 1: 3_ (3-tert-butoxycarbonylmethoxy

標題化合物係經由用以製備（2s)-3-(4_第三·丁氧羰甲氧 基-苯基）-2\甲氧基-丙酸乙酯（製備物3、步驟丨）之相同方法 由3_(3_瘦基-苯基）-2_甲氧基-丙酸甲酯（實例9、步驟句製備 ’以生產黃色油。CnH24〇6[M+Hr之MS (ES) : 325。 步騾2 : 3_(3_羧甲氧基-苯基）_2-甲氧基_丙酸甲酯The title compound is the same as used to prepare (2s) -3- (4-tert-butoxycarbonylmethoxy-phenyl) -2 \ methoxy-propionic acid ethyl ester (Preparation 3, Step 丨) The method was prepared from 3_ (3-Leptyl-phenyl) -2_methoxy-propionic acid methyl ester (Example 9, step sentence 'to produce a yellow oil. CnH24〇6 [M + Hr MS (ES): 325 Step 2: 3_ (3_carboxymethoxy-phenyl) _2-methoxy_propionic acid methyl ester

標題化免#係經由用以製備（28)_3-(4_羧甲氧基-苯基）_2_ 甲氧基-丙酸乙酯（製備物3、步騾2)之相同方法由3_(3_第三_ 丁氧羰甲氧基·苯基>2_甲氧基-丙酸甲酯（製備物4、步驟〇 製備，以生產黃色油。Cl3Hl6〇6[M+H]+之ms(es): 269。 步驟3 : 3-(3-{[2-(4-乙基-苯基）-乙基胺甲醯基]_甲氧基卜苯 基）-2-甲氧基-丙酸（異構物 H3CXl-人。Title 化 ## Via the same method used to prepare (28) _3- (4_carboxymethoxy-phenyl) _2_methoxy-propionic acid ethyl ester (Preparation 3, Step 2) from 3_ (3 _Third_Butoxycarbonylmethoxy · phenyl > 2-Methoxy-propionic acid methyl ester (Preparation 4, Step 0) to produce a yellow oil. Cl3H1660 [M + H] + ms (es): 269. Step 3: 3- (3-{[2- (4-Ethyl-phenyl) -ethylaminomethylmethyl] -methoxyphenylphenyl) -2-methoxy- Propionic acid (isomer H3CXl-human.

CH. 85504.doc -39- 心越化合物係經由用以製備（2s，iR)_2_乙氧基-3n [2-(4-冬乳基4基）_乙基胺甲醯基]_乙氧基卜苯基）_丙酸（實 例1步風3)〈相同万法由3一(3叛甲氧基-苯基）冬甲氧基、 丙酸甲酿(製備物4、步”與2-(4-乙基-苯基）-乙基胺製備 以生產播色油。C22H27n〇5 [M+H]+之ms (ES) : 386。 製備物5 (2S)-2-甲氧基-3-[4仆甲基-1-辛基胺甲酸基-乙氧基）-苯基] -丙酸CH. 85504.doc -39- Shin-Etsu compounds are used to prepare (2s, iR) _2_ethoxy-3n [2- (4-Winter milk-based 4-yl) _ethylamine formamyl] _ethyl Phenyl phenyl) _propionic acid (Example 1 step 3) <same method from 3 1 (3 methoxy-phenyl) winter methoxy, propionic acid methyl ester (preparation 4, step "and Preparation of 2- (4-ethyl-phenyl) -ethylamine to produce a seed oil. C22H27n05 [M + H] + ms (ES): 386. Preparation 5 (2S) -2-methoxy 3- [4-Bromomethyl-1-octylcarbamate-ethoxy) -phenyl] -propionic acid

步騾1 : (2S)-3-[4-(l-第三-丁氧羰基-丨-甲基-乙氧基 &gt; 苯基] -2-甲氧基-丙酸乙酯Step 1: (2S) -3- [4- (l-Third-butoxycarbonyl- 丨 -methyl-ethoxy &gt; phenyl) -2-methoxy-propionic acid ethyl ester

標題化合物係經由用以製備（2S)-3-(4-第三-丁氧碳甲氧 基-苯基）-2-甲氧基·丙酸乙酯（實例121、步騾1)之相同方法The title compound is the same as used to prepare (2S) -3- (4-Third-butoxycarbmethoxy-phenyl) -2-methoxypropionate (Example 121, Step 1) method

由（2S)-3-(4-羥基·苯基）-2-甲氧基-丙酸酯（實例1、步驟丨）與 2 -溪-2·甲基-丙酸弟二-丁 @旨製備’以生產育色油。〖H-nmR (CDC13, 200.15 MHz) ·· []7·10 (d，2H，J=8.3)，6·77 (d，2H， J=8.3)，4.17 (c，2H，J=6.9)，3.90 (t，lH，J=6.5)，3.34 (s, 3H)， 2.93 (d，2H，J=6.5)，1.55 (s，3H)，1.43 (s，9H)，1·23_ι·4 (t，3H， -40- 85504.doc 200406371 J=6.9) 〇 步驟2 : (2S)-3-[4-(l-幾基甲基_乙氧基）_苯基p2_甲氧基_ 丙酸乙酯From (2S) -3- (4-hydroxy · phenyl) -2-methoxy-propionate (Example 1, step 丨) and 2-xi-2 · methyl-propionate Prepared to produce a coloring oil. [H-nmR (CDC13, 200.15 MHz) · [] 7 · 10 (d, 2H, J = 8.3), 6.77 (d, 2H, J = 8.3), 4.17 (c, 2H, J = 6.9) , 3.90 (t, 1H, J = 6.5), 3.34 (s, 3H), 2.93 (d, 2H, J = 6.5), 1.55 (s, 3H), 1.43 (s, 9H), 1.23_ι · 4 ( t, 3H, -40- 85504.doc 200406371 J = 6.9) 〇 Step 2: (2S) -3- [4- (l-Ethylmethyl_ethoxy) _phenyl p2_methoxy_propane Ethyl acetate

標題化合物係經由用以製備（2S)-3_(4-羧甲氧基_苯基 甲氧基-丙酸乙酯（實例121、步騾2)之相同方法由（2S)_3_ 了φ [4-(1-第三-了氧羰基q•甲基_乙氧基苯基卜2_甲氧基_丙酸子 乙酿（製備物5、步驟1)製備，以生產黃色油。iH-N]v1r (CDC13， 200.15 MHz): 7·1〇 (d，2H，J=8.3)，6·77 (d，2H，J=8.3)，4.14 (c， 2H，J=6.9)，3·89 (t，1H，J=6.5)，3·34 (s，3H)，2·94 (d，2H， J=6.5)，1.55 (s，6H)，1·19 (t，3H，J=6.9)。 步驟3: (2S)-2_甲氧基-3_[4_(1-甲基_丨_辛基胺甲醯基_乙氧基） -苯基]-丙酸The title compound was prepared from (2S) _3_ by φ [4 via the same method used to prepare (2S) -3_ (4-carboxymethoxy_phenylmethoxy-propionic acid ethyl ester) (Example 121, Step 2). -(1-Third-oxocarbonyl q • methyl_ethoxyphenylbuth 2-methoxy_propionate) (Preparation 5, Step 1) to produce a yellow oil. IH-N ] v1r (CDC13, 200.15 MHz): 7.10 (d, 2H, J = 8.3), 6.77 (d, 2H, J = 8.3), 4.14 (c, 2H, J = 6.9), 3.89 (t, 1H, J = 6.5), 3.34 (s, 3H), 2.94 (d, 2H, J = 6.5), 1.55 (s, 6H), 1.19 (t, 3H, J = 6.9 ) Step 3: (2S) -2_methoxy-3_ [4_ (1-methyl_ 丨 _octylaminemethylamidino_ethoxy) -phenyl] -propionic acid

對掌體Palm body

標題化合物係經由用以製備（2S，1R)-2•乙氧基_3_(4_〇 [2-(4-苯氧基-苯基）_乙基胺甲醯基乙氧基卜苯基丙酸（實 例1、步驟3)之相同方法由（2S)_3-[4_(1_羧基甲基_乙氧^ 苯基]-2-甲氧基-丙酸乙酯（製備物5、步驟2)與庚胺製備，以 85504.doc -41- 200406371 生產無色油。C21H33N05 [M+H]+之 MS (ES) : 380。 — 實例1 (2S，l’R)-2 -乙氧基-3-(4-{1’-[2-(4·苯氧基-苯基）-乙基胺甲 醯基]-乙氧基卜苯基）-丙酸 對掌體The title compound is used to prepare (2S, 1R) -2 • ethoxy_3_ (4_〇 [2- (4-phenoxy-phenyl) _ethylaminomethylamidoethoxyphenylphenyl The same method for propionic acid (Example 1, step 3) consists of (2S) _3- [4_ (1_carboxymethyl_ethoxy ^ phenyl] -2-methoxy-propionic acid ethyl ester (Preparation 5, step 2) Preparation with heptylamine to produce colorless oil at 85504.doc -41- 200406371. MS (ES) of C21H33N05 [M + H] +: 380. — Example 1 (2S, l'R) -2 -ethoxy -3- (4- {1 '-[2- (4 · phenoxy-phenyl) -ethylaminomethyl] -ethoxybuphenyl) -propionic acid

步騾1 : (2R，l’R)_3-[(4-(l’·苄氧羰基-乙氧基）_苯基]_2·乙氧 基-丙酸乙酉旨Step 1: (2R, l’ R) _3-[(4- (l '· benzyloxycarbonyl-ethoxy) _phenyl] _2 · ethoxy-propionic acid ethyl ester

標題化舍二物係經由用以製備（2S)-3-[4-(3-溴基_丙氧基）_ 苯基]-2-甲氧基-丙酸乙酯（製備物1、步驟2)之相同方法由 2(S)-2-乙氧基-3-(4-羥基-苯基）_丙酸甲酯（製備物2之異構物The title compound is used to prepare (2S) -3- [4- (3-bromo_propoxy) _phenyl] -2-methoxy-propionic acid ethyl ester (Preparation 1, Step 2) Same method from 2 (S) -2-ethoxy-3- (4-hydroxy-phenyl) _propionic acid methyl ester (isomer of Preparation 2

1V10 ·外ιο·ζ，[lvi卞iNaj : 423.2。1V10 · Outer · · ζ, [lvi 卞 iNaj: 423.2.

丙酸 85504.doc 42- 200406371Propionate 85504.doc 42- 200406371

標題化合物係經由用以製備3_(3_羥基-苯基）甲氧基、 丙酸甲酯（實例9、步驟4)之相同方法由（2S，1R)_3-[4-(l-苄氧 羰基-乙氧基）-苯基]-2-乙氧基-丙酸乙酯（實例丨、步騾丨）製備 ’以生產黃色油。C16H?2〇6 [m+NH4]+之MS (ES) : 328·2。The title compound was prepared from (2S, 1R) _3- [4- (l-benzyloxy) via the same method used to prepare 3- (3-hydroxy-phenyl) methoxy, methyl propionate (Example 9, step 4). Carbonyl-ethoxy) -phenyl] -2-ethoxy-propionic acid ethyl ester (Example 丨, Step 骡 丨) was prepared to produce a yellow oil. MS (ES) for C16H? 206 [m + NH4] +: 328.2.

步驟3 ·· (2S，一 l’R)-2_乙氧基_3兴4-{1，_[2_(心苯氧基_苯基）_乙7鲁 基胺甲醯基f-乙氧基}苯基）·丙酸 SStep 3 · · (2S, 1'R) -2_ethoxy_3Xing 4- {1, _ [2_ (cardiphenoxy_phenyl) _ethyl 7 luthylamine methylamido f-ethyl Oxy} phenyl) propionic acid S

(實例1、步巧2)(0.1毫莫耳）溶於16 χ 1〇〇 mm試管中之二氯巧 甲烷，添加三乙胺（0·15毫莫耳）、二甲基胺基吡啶（〇〇1毫莫〜 耳）、PyBroP (0.2毫莫耳）與2-(4-苯氧基·苯基乙胺（〇15毫 莫耳），並令混合物於室溫隔夜攪拌。於真空中濃縮混合物 至乾。溶粗產物於MeOH，並填充入500毫克scx管柱（以、 MeOH預調整）。以Me0H洗管柱（2χ2毫升）。濃縮粗產物，， 並令殘渣於乙醇（2毫升）與Na0H(1莫耳濃度水溶液、丨毫升） 混合物中重組，令其於室溫攪拌直至經1〇&gt;1^：_1^3顯示水解 完成為止。然後，添加HC1 (1莫耳濃度水溶液）（直至{&gt;11=3): 85504.doc -43- 200406371 ’並減塾消滅溶液。令殘渣於CH2C12/H20重組，並濾過厭 水性注4士铃、 为丁同 &gt;分離有機層、濃縮並經HPLC-MS純化，以生 產無色油之化合物。C28H31N06 [M+H]+之MS (ES) : 478·2。 實例2 )2乙氣基- 3- (4·{1’[2_(4 -乙基-苯基)-乙基胺甲酸基] -乙氧基卜苯基）-丙酸 對掌體(Example 1, Step 2) (0.1 mmol) Dichloromethane dissolved in a 16 x 100 mm test tube, and triethylamine (0.15 mmol), dimethylaminopyridine ( 〇〇Ιmmol ~ ear), PyBroP (0.2mmol) and 2- (4-phenoxy · phenylethylamine (〇15mmol)), and the mixture was stirred overnight at room temperature. Under vacuum The mixture was concentrated to dryness. The crude product was dissolved in MeOH and packed into a 500 mg scx column (pre-adjusted with MeOH). The column was washed with MeOH (2 x 2 ml). The crude product was concentrated and the residue was taken up in ethanol (2 ml ) And Na0H (1 molar solution, 1 ml) and reconstituted at room temperature until the hydrolysis is completed at 10> 1 ^: _ 1 ^ 3. Then, HC1 (1 molar solution) is added. ) (Until {&gt; 11 = 3): 85504.doc -43- 200406371 'and reduce the elimination solution. The residue was reconstituted in CH2C12 / H20, and filtered through an anaerobic injection of 4 Shizuo, for Dingtong> separation of the organic layer , Concentrated and purified by HPLC-MS to produce the compound as a colorless oil. MS (ES) of C28H31N06 [M + H] +: 478 · 2. Example 2) 2 Ethyl-3- (4 · {1 '[ 2_ (4- Yl - phenyl) - ethylamine acid-yl] - ethoxy Bu phenyl) - propionic acid palm member

才求7^化合物係經由用以製備（2S，l，R)-2-乙氧基-3-(4-{Γ-[2-(4_苯氧基_笨基）_乙基胺甲醯基]-乙氧基}苯基）-丙酸（實 例1、步驟3)之相同方法由2-(4-乙基-苯基）-乙胺與（2S， l’R)-3-[4-(r-羧基-乙氧基）-苯基]乙氧基-丙酸（實例卜步 驟2)製備，以生產無色油。C24H31N05 [M+H]+之MS (ES): 414.2。 ~ 實例3 (2S, rR)-2-乙氧基_3-(4·{1’-[2_(4·三氟甲基-苯基）-乙基胺 甲醯基]-乙氧基卜苯基）-丙酸 ΟΗThe 7 ^ compound was used to prepare (2S, l, R) -2-ethoxy-3- (4- {Γ- [2- (4_phenoxy_benzyl) _ethylamine methyl Fluorenyl] -ethoxy} phenyl) -propionic acid (Example 1, step 3) The same method was used for 2- (4-ethyl-phenyl) -ethylamine and (2S, l'R) -3- [4- (r-carboxy-ethoxy) -phenyl] ethoxy-propionic acid (Example 2 step 2) was prepared to produce a colorless oil. C24H31N05 [M + H] + MS (ES): 414.2. ~ Example 3 (2S, rR) -2-ethoxy-3- (4 · {1 '-[2_ (4 · trifluoromethyl-phenyl) -ethylaminomethylmethyl] -ethoxy Phenyl) -propionate

85504.doc -44- 20040637185504.doc -44- 200406371

標越化合物係經由用以製備（2S，l，R)_2_乙氧基_3彳4·”，· [2_(‘苯氧基t苯基）_乙基胺甲醯基]-乙氧基}苯基）_丙酸（實 例1、步騾3)之相同方法由2-(4-三氟甲基-苯基）-乙基胺與 (2S，l’K)-3_[‘（i’_羧基-乙氧基）_苯基]_2_乙氧基_丙酸（實例 1、步驟2)製備，以生產無色油。C23H26F3N05 [Μ+Η]+之MS (ES) : 454.2, [M-H]· : 452.2。 實例4 (23’1’1〇_3_{4_[1’_(4_第'三-丁基-環己基胺甲醯基）-乙氧基]-- 苯基}-2-乙氧基-丙酸The standard crossover compound is used to prepare (2S, l, R) _2_ethoxy_3 彳 4 · ", · [2 _ ('phenoxytphenyl) _ethylaminemethylmethyl] -ethoxy Group} phenyl) _propionic acid (Example 1, step 3) The same method was used from 2- (4-trifluoromethyl-phenyl) -ethylamine and (2S, l'K) -3 _ ['( i'_carboxy-ethoxy) _phenyl] _2_ethoxy_propionic acid (Example 1, step 2) was prepared to produce a colorless oil. C23H26F3N05 [Μ + Η] + MS (ES): 454.2, [MH] ·: 452.2. Example 4 (23'1'1〇_3_ {4_ [1 '_ (4_'th-butyl-cyclohexylaminemethylamidino) -ethoxy]-phenyl } -2-ethoxy-propionic acid

OHOH

h3c」 標題化合物係經由用以製備（2S，1，R)_2-乙氧基-3-(4-{1，-[2-(4-苯氧基-苯基）_乙基胺甲醯基]-乙氧基}苯基）-丙酸（實 例1、步騾3)之相同方法由4-第三·丁基-環己胺之順/反（2 : 3)混合物與DS，1，R)_3-[4_(1，-羧基-乙氧基）_苯基]_2_乙氧基 -丙酸（實例1、步騾2)製備，以生產無色油。c24H37N05 [M+H] + 之MS (ES) : 420.03, [M+NH4]+ : 442·3, [Μ十H]+ ·· 418.2。 實例5 (2S，l’R)-2·乙氧基·3_(4·{ΐ，·[2-(2-乙氧基-苯基）-乙基胺甲 醯基l·乙氧基卜苯基）-丙酸 85504.doc •45- 200406371h3c ”The title compound is used to prepare (2S, 1, R) _2-ethoxy-3- (4- {1,-[2- (4-phenoxy-phenyl) _ethylamine formamidine Group] -ethoxy} phenyl) -propionic acid (Example 1, step 3) The same method was used for a cis / trans (2: 3) mixture of 4-tert-butyl-cyclohexylamine with DS, 1 , R) _3- [4_ (1, -carboxy-ethoxy) _phenyl] _2_ethoxy-propionic acid (Example 1, Step 2) to produce a colorless oil. c24H37N05 [M + H] + MS (ES): 420.03, [M + NH4] +: 442.3, [Μ 十 H] + · 418.2. Example 5 (2S, l'R) -2 · ethoxy · 3_ (4 · {ΐ, · [2- (2-ethoxy-phenyl) -ethylaminomethylmethyl-1 · ethoxybenzene Phenyl) -propionic acid 85504.doc • 45- 200406371

標題化合物係經由用以製備（2S，l，R)-2_乙氧基-3-(4-{1、 -φ [2-(4-苯氧奏〜苯基）_乙基胺甲醢基]-乙氧基}苯基）-丙酸（實7&quot; 例1、步驟3.X相同方法由2_(2-乙氧基-苯基卜乙基胺與（2S， l’R)_3-[4-(l’·羧基_乙氧基苯基]_2_乙氧基-丙酸（實例卜步 騾2)製備，以生產無色油。C24H31N〇6 [M+H]+之MS (ES): 430.2 〇 實例6The title compound is used to prepare (2S, l, R) -2-ethoxy-3- (4- {1, -φ [2- (4-phenoxy ~ phenyl) _ethylamine formamidine) Group] -ethoxy} phenyl) -propionic acid (Act 7 &quot; Example 1, Step 3.X In the same way, 2_ (2-ethoxy-phenylbuthylamine and (2S, l'R) _3- [ 4- (l '· carboxyl_ethoxyphenyl] _2_ethoxy-propionic acid (example b) 骡 2) to produce a colorless oil. C24H31N〇6 [M + H] + MS (ES) : 430.2 〇 Example 6

(2S，l’R)-2-乙氧基·3-{4-[1，-(3-三氟甲基基胺甲醯基）-_ 乙氧基]-苯基}-丙酸 nu 對掌體(2S, l'R) -2-ethoxy · 3- {4- [1,-(3-trifluoromethylaminomethylamidino) -_ ethoxy] -phenyl} -propionic acid nu Palm body

標題化合物係經由用以製備（2S，1 ’R)_2-乙氧基-3-(4-{ 1 ， [2-(4-苯氧基-苯基）-乙基胺甲醯基]•乙氧基}苯基）-丙酸（實 例1、步驟3)之相同方法由3-三氟甲基·苄胺與（2S，l’R) -3-[4-(1，-羧基-乙氧基）-苯基]-2-乙氧基·丙酸（實例1、步驟〜 85504.doc -46- 200406371 2)製備 440.2 〇 以生產我色油。C22H24F3N〇5 [Μ+Η]+之 MS (ES) ·· (2S，l’R)_2_ 乙氧基 j 實例 Η-[Γ-(3-氟基·5-三氟甲基-芊基胺甲 酿基）_乙氧基]-苯基}-丙酸The title compound is used to prepare (2S, 1 'R) _2-ethoxy-3- (4- {1, [2- (4-phenoxy-phenyl) -ethylaminomethylmethyl]] Ethoxy} phenyl) -propionic acid (Example 1, Step 3) The same method was used for 3-trifluoromethyl-benzylamine and (2S, l'R) -3- [4- (1, -carboxy- Ethoxy) -phenyl] -2-ethoxy · propionic acid (Example 1, step ~ 85504.doc -46- 200406371 2) Preparation of 440.2 〇 to produce a color oil. MS (ES) of C22H24F3NO5 [M + Η] + (2S, l'R) _2_ethoxyj Example Η- [Γ- (3-Fluoro-5-trifluoromethyl-fluorenylamine (Methyl alcohol) _ethoxy] -phenyl} -propionic acid

對掌體 標題化人私# 〇勿係、、呈由用以製備（2S，l，R)-2-乙氧基-3_(4_{Γ-[2-(4-苯氧義# &quot;^冬暴）·乙基胺甲醯基]-乙氧基}苯基）-丙酸（實 例1、步.驟3)、 一 λ 相同方法由3-氟基-5-三氟甲基-芊胺與（2S， 1 R)_3-[4_(1，多 1 久I-乙氧基）·苯基]_2_乙氧基-丙酸（實例1、步 驟2)製備， ^ 玍屋鴂色油。C22H23F4N05 [Μ-ΗΓ 之 MS (ES) :456.1。 ，❿ 實例8 (2S，1 ’R)i( ”_丨1 -[(二苯基_3_基甲基）·胺甲醯基]•乙氧基卜 笨基）-2-乙氧基-丙酸 對掌體 標題To the palm body title of human private # 〇 Do not be, and used to prepare (2S, l, R) -2-ethoxy-3_ (4_ {Γ- [2- (4-phenoxyyi # &quot; ^ Winter storm) · Ethylaminomethylmethyl] -ethoxy} phenyl) -propionic acid (Example 1, step. Step 3), λ Same method from 3-fluoro-5-trifluoromethyl- Preparation of amidamine with (2S, 1 R) _3- [4_ (1, more than 1 long I-ethoxy) · phenyl] _2_ethoxy-propionic acid (Example 1, step 2), ^ 玍 屋 鴂Color oil. C22H23F4N05 [MS (ES) of Μ-ΗΓ: 456.1. , ❿ Example 8 (2S, 1 'R) i (”_ 丨 1-[(Diphenyl_3_ylmethyl) · carbamoyl] • ethoxybenzyl) -2-ethoxy -Propionate palmar title

OHOH

化合物係經由用以製備（2S，l，R)-2-乙氧基-3-(4-{1 9 一 85504.doc -47- 200406371 [2-(4-苯氧基-苯基）-乙基胺甲醯基]•乙氧基}苯基）_丙酸（實 例1、步驟盯之相同方法由C-二苯基_3_基-甲胺與（2S，今 l’R)-3-[4-(l，-羧基-乙氧基）-苯基]-2-乙氧基·丙酸（實例1、步 驟2)製備，以生產無色油。c27H29N05 [M+H]+之MS (ES) ·· &quot; 448·2 〇 實例9 (2S，1’11)-3-(4-{1’-[2-(3_氯基-苯基)-乙基胺甲醯基]-乙氧基} -苯基^ )-2-乙氧基-丙酸 了jThe compound is used to prepare (2S, l, R) -2-ethoxy-3- (4- {1 9-85504.doc -47- 200406371 [2- (4-phenoxy-phenyl)- Ethylaminomethylamidino] • ethoxy} phenyl) _propionic acid (Example 1, the same method as in the step, from C-diphenyl_3_yl-methylamine and (2S, present l'R)- 3- [4- (l, -carboxy-ethoxy) -phenyl] -2-ethoxy · propionic acid (Example 1, step 2) was prepared to produce a colorless oil. C27H29N05 [M + H] + of MS (ES) · &quot; 448 · 2 〇 Example 9 (2S, 1'11) -3- (4- {1 '-[2- (3-chloro-phenyl) -ethylaminomethylmethyl ] -Ethoxy} -phenyl ^)-2-ethoxy-propionic acid

標題化合物係經由用以製備（2S，l，R)-2-乙氧基-3-(4-{Γ-[2_(4_苯氧轰·苯基）-乙基胺甲醯基]-乙氧基}苯基）·丙酸（實 例1、步驟3)之相同方法由2-(3_氯基-苯基乙基胺與（2S， _ l’R)-3-[4-(l’_羧基-乙氧基&gt;苯基乙氧基-丙酸（實例丨、步 驟2)製備’以生產無色油。c22H26C1N〇5 [μ+ΗΓ之MS (ES) :420.2 〇 實例10 (2S，l’R)_2-乙氧基·3·(4_{ΐ，_[2-(3-氟基-苯基）-乙基胺甲醯 基]-乙氧基卜苯基）-丙酸 85504.doc -48- 200406371 對掌體The title compound is used to prepare (2S, l, R) -2-ethoxy-3- (4- {Γ- [2_ (4-phenoxybenzylphenyl) -ethylaminomethylmethyl]- Ethoxy} phenyl) propionic acid (Example 1, step 3) The same method was used from 2- (3-chloro-phenylethylamine and (2S, _l'R) -3- [4- ( l'_carboxy-ethoxy &gt; phenylethoxy-propionic acid (Example 丨, step 2) was prepared to produce a colorless oil. c22H26C1N〇5 [MS (ES) of + + Γ: 420.2 〇 Example 10 ( 2S, l'R) _2-ethoxy · 3 · (4_ {ΐ, _ [2- (3-fluoroyl-phenyl) -ethylaminomethylmethyl] -ethoxyphenylphenyl) -propyl Acid 85504.doc -48- 200406371 on palm body

OHOH

&amp;遣化合物係經由用以製備（2S, pRK乙氧基|(心{卜 [2-(4-苯氧基_笨基）_乙基胺甲醯基]-乙氧基丨苯基）_丙酸（實一 :&quot;’步知3、L之相同方法由[2·(3_氟基_苯基乙基]甲基_胺上· 與（2S，l’R)-3’_(1，_叛基·乙氧基）_苯基卜2_乙氧基丙酸（實 例1、步驟2)製備，以生產無色油。C22H26FN05 [M+H] +之 MS (ES) ·· 404.2 〇 實例11 (2S，l’R)-2-乙氧基-3 — (4_{1、[2_(2_氟基·苯基）_乙基胺甲醯 基]-乙氧基}-苯基）-丙酸&amp; compounds are used to prepare (2S, pRK ethoxy | (Heart {Bu [2- (4-phenoxy_benzyl) _ethylaminomethylmethyl] -ethoxy 丨 phenyl) _Propionic acid (real one: &quot; 'step know 3, L in the same way by [2 · (3_fluoro group_phenylethyl] methyl_amine on and (2S, l'R) -3' _ (1, _Beryl · ethoxy) _Phenylbenzene 2_Ethoxypropionic acid (Example 1, Step 2) to produce a colorless oil. C22H26FN05 [M + H] + MS (ES) · · 404.2 〇 Example 11 (2S, l'R) -2-ethoxy-3 — (4_ {1, [2_ (2-fluoro group · phenyl) _ethylaminomethylmethyl] -ethoxy} -Phenyl) -propionic acid

41 標題化合物係經由用以製備（2S，l，R)-2·乙氧基-3-(4-{Γ-[2-(4_苯氧基·苯基）-乙基胺甲醯基]-乙氧基}苯基）-丙酸（實 例1、步驟3)之相同方法由[2_(2_氟基·苯基）_乙基卜甲基_胺 : 85504.doc -49- 200406371 與（2S，l’R)-3_[4彳Γ_羧基-乙氧基）_苯基]-2-乙氧基-丙酸（實 例1、步驟2燦備，以生產無色油。c22H26FN05 [Μ+Η] +之 MS (ES) : 404.2。 實例12 (2S，l’R)-3-(‘二氯基-苯基）_乙基胺甲醯基]-乙 氧基卜苯基）-2-乙氧基-丙酸 OH 對掌體41 The title compound was prepared via (2S, l, R) -2 · ethoxy-3- (4- {Γ- [2- (4-phenoxy · phenyl) -ethylaminomethylmethyl) ] -Ethoxy} phenyl) -propionic acid (Example 1, step 3) The same method was used for [2_ (2_Fluoro · phenyl) _ethylbumethyl_amine: 85504.doc -49- 200406371 and ( 2S, l'R) -3_ [4 彳 Γ_carboxy-ethoxy) _phenyl] -2-ethoxy-propionic acid (Example 1, step 2 is brilliant to produce a colorless oil. C22H26FN05 [Μ + Η] + MS (ES): 404.2. Example 12 (2S, l'R) -3-('dichloro-phenyl) -ethylaminomethylmethyl] -ethoxyphenylphenyl) -2 -Ethoxy-propionic acid OH on palm body

標題化合物係經由用以製備（2S，l，R)-2-乙氧基-3-(4-{1，-[2_(4_苯氧基-苯基）-乙基胺甲醯基]-乙氧基}苯基）_丙酸（實 例1、步驟3)之相同方法由2_(2,4-二氯基-苯基）-乙胺與（2S， l’R)-3-[4-(l、羧基-乙氧基）_苯基]·2·乙氧基-丙酸（實例1、步 騾2)製備，—这生產無色油。C22H25C12N05[M+H] +之MS(ES) :454.1 〇 實例13 (28，1’11)-3-(4_{1’-[2-(2,6-二氯基-苯基）-乙基胺甲醯基]-乙 氧基卜苯基）-2-乙氧基-丙酸The title compound is used to prepare (2S, l, R) -2-ethoxy-3- (4- {1,-[2_ (4-phenoxy-phenyl) -ethylaminomethylmethyl] -Ethoxy} phenyl) -propionic acid (Example 1, step 3) The same method was used for 2- (2,4-dichloro-phenyl) -ethylamine and (2S, l'R) -3- [ 4- (l, carboxy-ethoxy) -phenyl] · 2 · ethoxy-propionic acid (Example 1, Step 2) was prepared, which produced a colorless oil. MS (ES) of C22H25C12N05 [M + H] +: 454.1 〇 Example 13 (28,1'11) -3- (4_ {1 '-[2- (2,6-dichloro-phenyl) -ethyl Aminomethylformyl] -ethoxyphenylphenyl) -2-ethoxy-propionic acid

對掌體 85504.doc • 50- 200406371 標題化合物係經由用以製備（2S，l’R)-2_乙氧基-3-(4-{l’-[2-(4-苯氧基^苯基）_乙基胺甲醯基]-乙氧基}苯基）-丙酸（實 例1、步驟3)之相同方法由2-(2，6-二氣基-苯基）-乙胺與（2S， 1’Κ〇·3·[4-(Γ_叛基-乙氧基）-苯基]-2-乙氧基丙酸（實例卜步 驟2)製備，以生產無色油。C22H25C12N05[M+H]+之MS(ES) :454.1 〇 實例14 (2S，1 ’R)_2 -乙氧基_3-[4-(1 庚基胺甲酸基-乙氧基）-苯基]-: 丙酸 …〜 對掌體Counterpart 85504.doc • 50- 200406371 The title compound is used to prepare (2S, l'R) -2_ethoxy-3- (4- {l '-[2- (4-phenoxy ^) Phenyl) -ethylamine methylamidino] -ethoxy} phenyl) -propionic acid (Example 1, step 3) from 2- (2,6-diamino-phenyl) -ethylamine Prepared with (2S, 1′Κ〇 · 3 · [4- (Γ_ 叛 基 -ethoxy) -phenyl] -2-ethoxypropionic acid (Example 2 step 2) to produce a colorless oil. C22H25C12N05 [M + H] + MS (ES): 454.1 〇 Example 14 (2S, 1 'R) _2 -ethoxy_3- [4- (1 heptylaminocarboxylate-ethoxy) -phenyl] -: Propionic acid ... ~ On palm

標題化合物係經由用以製備（2S，l’R)-2-乙氧基-3-(4-{1，-[2-(4-苯氧毛-苯基卜乙基胺甲醯基]-乙氧基}苯基）·丙酸（實 例1、步驟3)之相同方法由庚胺與（2S，1 ’R)_3-[4-(l 瘦基-乙氧基）-苯基]-2-乙氧基-丙酸（實例1、步驟2)製備，以生產 無色油。C21H33N〇5 [M+H]+之MS (ES) : 380.3。 實例15 (2s，氯基-笨基)-乙基胺甲醯基]-乙氧基} -苯基）-2-乙氧基-丙酸 85504.doc -51- 200406371The title compound is used to prepare (2S, l'R) -2-ethoxy-3- (4- {1,-[2- (4-phenoxy hair-phenylbethylaminemethylmethyl) -ethyl Oxy} phenyl) propionic acid (Example 1, step 3) The same method was used for heptylamine and (2S, 1 'R) _3- [4- (l Leptyl-ethoxy) -phenyl] -2 -Ethoxy-propionic acid (Example 1, step 2) to produce a colorless oil. MS (ES) of C21H33NO5 [M + H] +: 380.3. Example 15 (2s, chloro-benzyl)- Ethylaminomethylmethyl] -ethoxy} -phenyl) -2-ethoxy-propionic acid 85504.doc -51- 200406371

對掌體 標題化合物係經由用以製備（2S，1，R)_2-乙氧基-3-(4-{1、 [2-(4-苯氧基-苯基）-乙基胺甲醯基]_乙氧基}苯基）_丙酸（實 例1、步騾之相同方法由2_(2-氯基-苯基）-乙胺與（2S， l’R)-3-[4-(l’-羧基-乙氧基&gt;苯基]-2·乙氧基-丙酸（實例卜步 騾2)製備，以生產無色油。c22H26C1N05 [M+H]+之MS (ES) 二 420.2 〇 實例16 (28，1’11)-3-(4{1，-[2-(4-第三-丁基-苯基）_乙基胺甲醯基]-乙 氧基}-苯基）-2 -乙氧基-丙酸 對掌體The title compound of palmar is used to prepare (2S, 1, R) _2-ethoxy-3- (4- {1, [2- (4-phenoxy-phenyl) -ethylamine formamidine Group] _ethoxy} phenyl) _propionic acid (Example 1, the same method of step 骡 from 2- (2-chloro-phenyl) -ethylamine and (2S, l'R) -3- [4- (l'-Carboxy-ethoxy &gt; phenyl] -2 · ethoxy-propionic acid (Example C. Step 2) to produce a colorless oil. c22H26C1N05 [M + H] + MS (ES) II 420.2 〇 Example 16 (28,1'11) -3- (4 {1,-[2- (4-Third-butyl-phenyl) _ethylaminomethylmethyl] -ethoxy} -benzene ) -2 -ethoxy-propionic acid on palm body

標題化合物係經由用以製備（2S，l，R)-2-乙氧基-3-(4-{1，-[2-(4_苯氧基·苯基）-乙基胺甲醯基l·乙氧基}苯基）_丙酸（實 例1、步騾3)之相同方法由第三-丁基-苯基）_乙胺與（2S， 1 R)-3-[4-(l _幾基·乙氧基）_苯基]-2-乙氧基-丙酸（實例1、步 驟2)製備，以生產無色油。c26H35NO [M+H]+之MS (ES) ·· 85504.doc -52- 200406371 ：442.5 〇 實例17 (2S，l’R)-2-乙氧基_3_{4-[1，_(4_氟基_爷基胺甲醯基）_乙氧 基]&quot;苯基}-丙酸The title compound is used to prepare (2S, l, R) -2-ethoxy-3- (4- {1,-[2- (4-phenoxy · phenyl) -ethylaminomethylmethyl) l · ethoxy} phenyl) _propionic acid (Example 1, step 骡 3) the same method from the third-butyl-phenyl) _ethylamine and (2S, 1 R) -3- [4- ( l _Jiji · ethoxy) _phenyl] -2-ethoxy-propionic acid (Example 1, step 2) to produce a colorless oil. MS (ES) of c26H35NO [M + H] + 85504.doc -52- 200406371: 442.5 〇 Example 17 (2S, l'R) -2-ethoxy_3_ {4- [1, _ (4 _Fluoro group_methylaminomethyl) _ethoxy] &quot; phenyl} -propionic acid

標題化合勘係經由用以製備（2S，l，R)-2-乙氧基_3_(4-{Γ-[2-(4-苯氧基·苯基）_乙基胺甲醯基乙氧基丨苯基）_丙酸（實 例1、步驟3)之相同方法由4-氟基-爷胺與（2S，l，R)-3_[4-(l，-叛基-乙氧基）_苯基]_2_乙氧基-丙酸（實例1、步騾2)製備，以 生產無色油。C21H24FN〇5 [M+H]+之MS (ES) : 390.4。 實例18 (2S，l’R)-2-乙氧基-3-{4-[l，-(4-三氟甲基-芊基胺甲醯基）· — 乙氧基]-苯基卜丙酸The title chemical system is used to prepare (2S, l, R) -2-ethoxy_3_ (4- {Γ- [2- (4-phenoxy · phenyl) _ethylaminomethylethylethyl) Oxy 丨 phenyl) _propionic acid (Example 1, step 3) The same method was used for 4-fluoro-ethanamine and (2S, l, R) -3_ [4- (l, -s-yl-ethoxy) ) _Phenyl] _2_ethoxy-propionic acid (Example 1, Step 2) to produce a colorless oil. MS for C21H24FN05 [M + H] + (ES): 390.4. Example 18 (2S, l'R) -2-ethoxy-3- {4- [l,-(4-trifluoromethyl-fluorenylaminomethylmethyl) · —ethoxy] -phenylbenzene Propionic acid

標題化合物係經由用以製備（2S，1 ’R)_2-乙氧基-3-(4-{1 [2-(4-苯氧基-苯基）-乙基胺甲醯基]-乙氧基}苯基）-丙酸（實 例1、步騾3)之相同方法由4-三氟甲基-芊胺與（2S，l’R) 85504.doc -53- 200406371 -3-[4-(l，-羧基·乙氧基）-苯基]-2-乙氧基·丙酸（實例1、步驟 2)製備，以全音無色油。C22H24F3N05 [M+H]+之MS (ES): 440.3 ° 實例19 (2S，l，R)-2-乙氧基-3-{4-[1，-(2_嘧吩-2-基-乙基胺甲醯基）· 乙氧基]-苯基卜丙酸 對掌體The title compound was prepared via (2S, 1 'R) _2-ethoxy-3- (4- {1 [2- (4-phenoxy-phenyl) -ethylaminomethylmethyl] -ethyl Oxy} phenyl) -propionic acid (Example 1, step 3) The same method was used for 4-trifluoromethyl-fluorenamine and (2S, l'R) 85504.doc -53- 200406371 -3- [4 -(l, -carboxy · ethoxy) -phenyl] -2-ethoxy · propionic acid (Example 1, step 2) was prepared as a whole tone colorless oil. C22H24F3N05 [M + H] + MS (ES): 440.3 ° Example 19 (2S, l, R) -2-ethoxy-3- {4- [1,-(2-pyrimin-2-yl- Ethylaminomethyl) · Ethoxy] -phenylbutyric acid palmitate

標題化合物係經由用以製備（2S，l，R)-2-乙氧基-3-(4-{1、 [2-(4-苯氧基-苯基）_乙基胺甲醯基&gt; 乙氧基}苯基）·丙酸（實 例1、步驟3)之相同方法由2-嘧吩-2-基-乙胺與（2S，l，R)-3-[4-( 1’_羧基-乙氧基）_苯基]-2-乙氧基-丙酸（實例1、步驟2) 製備，以生產黃色油。C2〇H25N05S [M+H]+之MS (ES) : 392.3。 實例20 (2S，l’R)_2_乙氧基_3-(4{1，-[卜塞吩-2_基_甲基）胺甲醯基]- 乙氧基}-苯基）-丙酸 對掌體The title compound is used to prepare (2S, l, R) -2-ethoxy-3- (4- {1, [2- (4-phenoxy-phenyl) _ethylaminomethylmethyl) &gt; Ethoxy} phenyl) · propionic acid (Example 1, step 3) The same method was used from 2-pyrimin-2-yl-ethylamine and (2S, l, R) -3- [4- (1 ' _Carboxy-ethoxy) _phenyl] -2-ethoxy-propionic acid (Example 1, step 2) was prepared to produce a yellow oil. MS for C20H25N05S [M + H] + (ES): 392.3. Example 20 (2S, l'R) _2_ethoxy_3- (4 {1,-[bustene-2_yl_methyl) aminomethylamino] -ethoxy} -phenyl)- Propionic acid

標題化合物係經由用以製備（2S，1，κ)-2_乙氧基_3-(4-{1，-[2-(4-苯氧基-苯基）-乙基胺甲醯基]_乙氧基丨苯基&gt;丙酸（實 85504.doc -54- 200406371 例1、步驟3)之相同方法由〇嘧吩-2-基-甲胺與（2S， l’R)_3-[4-(lL羧基_乙氧基）_苯基]-2_乙氧基-丙酸（實例卜步 驟2)製備，以生產黃色油。Ci9H23N〇5s [m+h]+之MS (ES) • 378·3 〇 實例21 (2S’ 第三-丁基-芊基胺甲醯基）·乙氧基]-苯 基}-2-乙氧基-丙酸The title compound is used to prepare (2S, 1, κ) -2_ethoxy_3- (4- {1,-[2- (4-phenoxy-phenyl) -ethylaminomethylmethyl) ] _Ethoxy 丨 Phenyl &gt; propionic acid (85504.doc -54- 200406371 Example 1, Step 3) The same method was used. 0 pyriphen-2-yl-methylamine and (2S, l'R) _3 -[4- (1L Carboxy_ethoxy) _phenyl] -2_ethoxy-propionic acid (Example 2 step 2) to produce a yellow oil. Ci9H23N05s [m + h] + MS ( ES) • 378.3. Example 21 (2S 'tertiary-butyl-fluorenylaminomethyl), ethoxy] -phenyl} -2-ethoxy-propionic acid

標題化合物作纟孩山 你心由用以製備(2S，l，R)-2_乙氧基-3_(4-{1，-[2 _ (4 -苯氯其# #、 冬基）_乙基胺甲醯基]_乙氧基丨苯基）_丙酸（實 例1、步辨3+ A )又相同方法由4-第三·丁基·苄胺與（2S，1，R) 3&quot;&quot;[4·(1 乙氧基）·苯基]-2·乙氧基·丙酸（實例1、步騾 2)製備，以1衾a么、L + 王產轶色油。C25H33N05 [M+H] +之 MS (ES): 428.4 〇 實例22 (2S’ 1 R)_3_{4_[l’-(4-第三-丁基-苯基胺甲醯基）·乙氧基]•苯 基}-2 -乙氧基-丙酸The title compound is used as a base for the preparation of (2S, l, R) -2_ethoxy-3_ (4- {1,-[2_ (4-phenylchloroqi ##, winter-based) _ Ethylamine methylamidino] _ethoxy 丨 phenyl) _propionic acid (Example 1, Step 3+ A) The same method was used from 4-third · butyl · benzylamine with (2S, 1, R) 3 &quot; &quot; [4 · (1 ethoxy) · phenyl] -2 · ethoxy · propionic acid (example 1, step 2) was prepared with 1 衾 a ?, L + Wang Yiyi oil. C25H33N05 [M + H] + MS (ES): 428.4 〇 Example 22 (2S '1 R) _3_ {4_ [l'-(4-Third-butyl-phenylaminomethylamidino) · ethoxy ] • phenyl} -2 -ethoxy-propionic acid

ch3 85504.doc -55- 200406371 標題化合物係經由用以製備（2S，l，R)-2-乙氧基_3-(4_{Γ_ [2-(4-苯氧基^笨基）_乙基胺甲醯基]-乙氧基丨苯基）_丙酸（實 例1、步驟3)之相同方法由4-第三-丁基-苯胺與（2S，l，R)-3-[心（1 -羧基-乙氧基）-苯基]-2-乙氧基-丙酸（實例1、步驟2)製 備’以生產無色油。C24H31N05 [Μ+Η] +之MS (ES) : 414.4。 實例23 (23’1’1〇-3-{‘[1’-(4_反式-第三_丁基-環己基胺甲醯基）_乙 氧基]-笨基}-2-乙氧基-丙酸ch3 85504.doc -55- 200406371 The title compound was used to prepare (2S, l, R) -2-ethoxy_3- (4_ {Γ_ [2- (4-phenoxy ^ benzyl) _ethyl Methylaminomethylmethyl] -ethoxy 丨 phenyl) -propionic acid (Example 1, step 3) from 4-third-butyl-aniline and (2S, l, R) -3- [Heart (1-Carboxy-ethoxy) -phenyl] -2-ethoxy-propionic acid (Example 1, step 2) was prepared to produce a colorless oil. C24H31N05 [M + Η] + MS (ES): 414.4. Example 23 (23'1'1〇-3-{'[1'-(4-trans-third-butyl-cyclohexylaminemethylamidino) _ethoxy] -benzyl} -2-ethyl Oxy-propionic acid

標題化合物係經由用以製備（2S，l，R)-2-乙氧基-3-(4-{Γ-[2-(4_苯氧基-苯基）-乙基胺甲醯基]-乙氧基}苯基）-丙酸（實 例1、步驟3)之相同方法由反式_4_第三-丁基-環己胺與（2S， l’R)_3_ [4-(1、羧基-乙氧基苯基]_2-乙氧基-丙酸（實例1、 步騾2)製備，以生產無色油。c24H37N05 [M+H]+之MS (ES) :420.3, [ΜΪΝΗ4]+ : 442.3 〇 實例24 (2S)-3-[4-({乙基_[&gt;(4-甲氧基-苯基）-1-甲基-乙基]-胺甲醯 基卜甲氧基）·苯基]-2_甲氧基-丙酸The title compound was prepared via (2S, l, R) -2-ethoxy-3- (4- {Γ- [2- (4-phenoxy-phenyl) -ethylaminomethyl) -Ethoxy} phenyl) -propionic acid (Example 1, step 3) The same method was used for trans_4_third-butyl-cyclohexylamine and (2S, l'R) _3_ [4- (1 , Carboxy-ethoxyphenyl] _2-ethoxy-propionic acid (Example 1, Step 2) to produce a colorless oil. C24H37N05 [M + H] + MS (ES): 420.3, [ΜΪΝΗ4] +: 442.3 〇 Example 24 (2S) -3- [4-({ethyl _ [&gt; (4-methoxy-phenyl) -1-methyl-ethyl] -carbamoylmethyl methoxy ) · Phenyl] -2-methoxy-propionic acid

對掌體 200406371 標題化合物係經由用以製備（2S，lR)-2-乙氧基 [2-(4-苯氧基苯基&gt; 乙基胺甲醯基]_乙氧基}苯基卜丙酸（實 例1、步騾3)义相同方法由（2以_3-(4_羧甲氧基-苯基）_2_甲氧 基-丙酸乙酯（製備物3、步驟2)與乙基-[2-(4_甲氧基_苯基）_卜 甲基-乙基]-胺製備，以生產無色油。c24H3iN〇6 [M+H]+之 MS (ES) : 430 〇 實例25Counterpart 200406371 The title compound is used to prepare (2S, lR) -2-ethoxy [2- (4-phenoxyphenyl &gt; ethylaminomethyl) -ethoxy} phenylbenzene Propionic acid (Example 1, step 3) is the same method as (2 to _3- (4_carboxymethoxy-phenyl) _2_methoxy-propionic acid ethyl ester (preparation 3, step 2) and Ethyl- [2- (4-methoxy_phenyl) _bumethyl-ethyl] -amine was prepared to produce a colorless oil. C24H3iN〇6 [M + H] + MS (ES): 430 〇 Example 25

(2S)-2-甲氧基-3-{4-[(1·審-1-基-乙基胺甲醯基）·甲氧基]苯 - 基}-丙酸(2S) -2-methoxy-3- {4-[(1 · tri-1-yl-ethylaminomethylmethyl) · methoxy] benzene-yl} -propionic acid

標題化合物係經由用以製備（2S，1R)-2_乙氧基_3_(4·。-[2-(4-苯氧基·苯基）_乙基胺甲醯基]_乙氧基}苯基）_丙酸（實 例1、步驟3)之相同方法由（2S)-3-(4-羧甲氧基-苯基）-2-甲氧 基-丙酸乙酯（製備物3、步驟2)與1-莕-1-基_乙胺製備，以生 產無色油。C24H25N〇5 [M+H]+之MS (ES) : 408。 實例26 (2S)-2-甲氧基-3-{4-[(l-苯基-乙基胺甲醯基）_甲氧 基]&quot;苯基}-丙酸The title compound is used to prepare (2S, 1R) -2_ethoxy_3_ (4 · .- [2- (4-phenoxy · phenyl) _ethylaminomethylmethyl] _ethoxy } Phenyl) _propionic acid (Example 1, step 3) The same method as (2S) -3- (4-carboxymethoxy-phenyl) -2-methoxy-propionic acid ethyl ester (Preparation 3 Step 2) Preparation with 1-fluoren-1-yl-ethylamine to produce a colorless oil. C24H25N05 [M + H] + MS (ES): 408. Example 26 (2S) -2-methoxy-3- {4-[(l-phenyl-ethylaminomethylmethyl) _methoxy] &quot; phenyl} -propionic acid

標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4-{l- - 85504.doc -57- 200406371 [2-(4-苯氧基-苯基）_乙基胺甲醯基乙氧基丨苯基）_丙酸（實 例1、步驟3)之相同方法由（28)〇-(4-羧甲氧基-苯基甲氧 基-丙酸乙酯（製備物3、步驟2)與1-苯基-乙胺製備，以生產 無色油。C20H23N〇5 [M+H]+之MS (ES) : 358。 實例27 (2S)-2-甲氧基_3-(4-{[甲基-(1-苯基-乙基胺甲醯基卜甲氧 基卜苯基）-丙酸The title compound is used to prepare (2S, lR) -2-ethoxy-3- (4- {l--85504.doc -57- 200406371 [2- (4-phenoxy-phenyl) _ethyl The same method for the aminoamine methylamidoxyethoxy phenyl) -propionic acid (Example 1, step 3) was obtained from (28) 0- (4-carboxymethoxy-phenylmethoxy-propionic acid ethyl ester ( Preparation 3, step 2) was prepared with 1-phenyl-ethylamine to produce a colorless oil. MS (ES) of C20H23N05 [M + H] +: 358. Example 27 (2S) -2-methoxy _3- (4-{[Methyl- (1-phenyl-ethylaminomethanemethylmethoxymethylphenyl) -propionic acid

標題化合物係經由用以製備（2S，1R)_2-乙氧基-3-(4-{1-[2-(4-苯氧基·苯基&gt; 乙基胺甲醯基]_乙氧基丨苯基丙酸（實 例1、步驟3)之相同方法由（2S)-3-(4-羧甲氧基-苯基）-2-甲氧 基-丙酸乙酉旨（製備物3、步騾2)與甲基_(1_苯基_乙基胺製備 ’以生產播色油。C21H25N05 [M+H]+之MS (ES) : 372。 _ 實例28 氟基-苄醯基）·哌啶_1_基]-2-氧基-乙氧 基}_苯基）-2-甲氧基-丙酸The title compound is used to prepare (2S, 1R) _2-ethoxy-3- (4- {1- [2- (4-phenoxy · phenyl &gt; ethylaminomethyl)]-ethoxy The same method for phenylpropionic acid (Example 1, step 3) was obtained from (2S) -3- (4-carboxymethoxy-phenyl) -2-methoxy-propionic acid ethyl acetate (Preparation 3, Step 2) Preparation with methyl_ (1-phenyl_ethylamine 'to produce a seed oil. MS (ES) of C21H25N05 [M + H] +: 372. _ Example 28 Fluoro-benzylfluorenyl) · Piperidine_1-yl] -2-oxy-ethoxy} _phenyl) -2-methoxy-propionic acid

〇 才717越化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4-{1- [2 (4苯氧基_笨基）_乙基胺甲醯基卜乙氧基丨苯基）_丙酸（實 例1、步驟&amp; h 相同方法由（2S)-3-(4-羧甲氧基-苯基）-2-甲氧 85504.doc -58- 200406371 基-丙酸乙酯（製備物3、步騾2)與（4-氟基-苯基）-哌啶-4-基- 甲酮製備，以-生產無色油。C24H26FN06 [M+H]+之MS (ES) :444 ° 實例29 (2S)-3-(4_{2-[4_(4_氯基·爷醯基）-哌啶小基]·2-氧基-乙氧基} -苯基）-2氧基-丙酸〇 才 717 越 Compound is used to prepare (2S, lR) -2-ethoxy-3- (4- {1- [2 (4phenoxy_benzyl) _ethylamine formamidine Oxy 丨 phenyl) _propionic acid (Example 1, step &amp; h) (2S) -3- (4-carboxymethoxy-phenyl) -2-methoxy 85504.doc -58- 200406371 -Ethyl propionate (Preparation 3, Step 2) and (4-fluoro-phenyl) -piperidin-4-yl-methanone to produce a colorless oil. C24H26FN06 [M + H] + of MS (ES): 444 ° Example 29 (2S) -3- (4_ {2- [4_ (4_ (Chloroyl · methylene) -piperidine small group] · 2-oxy-ethoxy} -benzene ) -2oxy-propionic acid

標題化舍物〜係經由用以製備（2S，lR)-2-乙氧基-3-(4-{1-[2-(4_苯氧基-苯基）-乙基胺甲醯基]-乙氧基}苯基）-丙酸（實 例1、步驟3)之相同方法由（2s)-3-(4-羧甲氧基-苯基）-2-甲氧 基-丙酸乙酯（製備物3、步驟2)與（4_氯基—苯基）_哌啶_4-基_ 甲酮製備’以生產黃色油。C24H26C1N06 [M+H]+之MS (ES) :460 ° 實例30 (2S)-2-甲氧”基_3-{4_[(1-甲氧羰基_2-苯基-乙基胺甲醯基）_ 甲氧基]-苯基}-丙酸The title compound is used to prepare (2S, 1R) -2-ethoxy-3- (4- {1- [2- (4-phenoxy-phenyl) -ethylaminomethylmethyl) ] -Ethoxy} phenyl) -propionic acid (Example 1, step 3) The same method was used for (2s) -3- (4-carboxymethoxy-phenyl) -2-methoxy-propionic acid ethyl Preparation of esters (Preparation 3, Step 2) with (4-chloro-phenyl) _piperidine_4-yl_methanone 'to produce a yellow oil. C24H26C1N06 [M + H] + MS (ES): 460 ° Example 30 (2S) -2-methoxy "yl_3- {4 _ [(1-methoxycarbonyl_2-phenyl-ethylamine formamidine) ) _Methoxy] -phenyl} -propionic acid

標題化合物係經由用以製備（2S，lR)-2_乙氧基-3·(4-{1-[2-(4_苯氧基-苯基）-乙基胺甲醯基]-乙氧基}苯基）-丙酸（實 85504.doc -59- 200406371 例1、步驟3)之相同方法由（2S)_3_㈠·叛甲氧基苯基）_2_甲氧 基-丙酸乙酉曰4製備物3、步驟2)與2_胺基_3_苯基_丙酸-甲酯 製備，以生產慼色油。C22H25N07 [M+H]+之 MS (ES) ·· 416。 實例3 1 (2S)-3-[4-(2-{4_[(4_氯基-苯基 &gt;苯基_甲基卜六輕吡畊^卜基} 氣基'&quot;乙氧基）-冬基]-2 -甲氧基·丙酸The title compound is used to prepare (2S, lR) -2-ethoxy-3 · (4- {1- [2- (4-phenoxy-phenyl) -ethylaminomethylmethyl] -ethyl Oxy} phenyl) -propionic acid (85504.doc -59- 200406371 Example 1, step 3) The same method is described by (2S) _3_㈠ · metmethoxymethoxyphenyl) _2_methoxy-propionic acid ethyl ester 4. Preparation 3, step 2) and 2-amino_3-phenyl-propionic acid-methyl ester to produce Qi colored oil. C22H25N07 [M + H] + MS (ES) 416. Example 3 1 (2S) -3- [4- (2- {4 _ [(4_Chloro-phenyl)> Phenyl_methylbuhexylpyridine ^ byl} Gas group '&quot; ethoxy ) -Dongyl] -2 -methoxy · propionic acid

標題化合物係經由用以製備（2S，1R)—2_乙氧基 [2-(4-苯氧基·苯基）_乙基胺甲醯基]_乙氧基}苯基）_丙酸（實 例1、步驟3)之相同方法由（2S)_3_(4_羧甲氧基_苯基甲氧 基-丙酸乙g旨（製備物3、步驟”與丨-“肛氯基_苯基）_苯基-甲 基]^辰併製備，以生產無色油。C29H31C1N205[M+H] +之MS (ES) : 524 〇 嫌 實例32 (2S)-3-[4-({[(4_氯基-苯基）_苯基-甲基]_胺甲醯基卜甲氧基） -苯基]-2-甲氧基-丙酸The title compound is used to prepare (2S, 1R) -2-ethoxy [2- (4-phenoxy · phenyl) _ethylaminomethylmethyl] _ethoxy} phenyl) _propionic acid (Example 1, step 3) The same method was used (2S) _3_ (4_carboxymethoxy_phenylmethoxy-propionic acid ethyl g) (Preparation 3, step "and (Phenyl) -phenyl-methyl] group and prepared to produce a colorless oil. MS (ES) of C29H31C1N205 [M + H] +: 524. Example 32 (2S) -3- [4-({[(( 4-Chloro-phenyl) _phenyl-methyl] _aminoformylbumethoxy) -phenyl] -2-methoxy-propionic acid

標題化合物係經由用以製備（2S，lR)-2·乙氧基-3-(4-{1- 85504.doc -60- 200406371 [2·(4-苯氧基-笨基）·乙基胺甲酸基]乙氧基}苯基）丙酸（實 例1、步騾3)毛相同方法由（2S)-3_(4-羧甲氧基-苯基）-2_甲氧 基-丙酸乙酯（製備物3、步騾2)與C-(4-氯基-苯基）-〇苯基- 甲胺製備’以生產黃色油。C25H24C1N05 [M+H]+之MS (ES) :454 〇The title compound is used to prepare (2S, 1R) -2 · ethoxy-3- (4- {1- 85504.doc -60- 200406371 [2 · (4-phenoxy-benzyl) · ethyl Carbamate] ethoxy} phenyl) propionic acid (Example 1, step 3) The same method is used for (2S) -3_ (4-carboxymethoxy-phenyl) -2_methoxy-propionic acid Preparation of ethyl ester (Preparation 3, Step 2) with C- (4-chloro-phenyl) -ophenyl-methylamine 'to produce a yellow oil. C25H24C1N05 [M + H] + MS (ES): 454 〇

實例32A (2S)-3-(4-{[丁基_(1_苯基-乙基）_胺甲醯基]_甲氧基卜苯基） _2_甲氧基-丙酸Example 32A (2S) -3- (4-{[butyl_ (1_phenyl-ethyl) _aminomethylmethyl] _methoxyphenylphenyl) _2_methoxy-propionic acid

標題化合物係經由用以製備（2S，lR)-2_乙氧基-3-(4-{l-[2_(4_苯氧基_苯基）_乙基胺甲醯基乙氧基丨苯基丙酸（實 例1 '步驟3)之相同方法由（2S)_3_(4_羧甲氧基_笨基）_2_甲氧 基-丙酸乙^製備物3、步驟2)與丁基-(1-苯基-乙基）-胺製備二_ ’以生產無克油。C24H31N05 [M+H] +之 MS (ES) : 414。 實例33 (2S)_3_{4_[(3,3·二苯基-丙基胺甲醯基）-甲氧基]-苯基卜2-甲 氧基-丙酸The title compound is used to prepare (2S, lR) -2_ethoxy-3- (4- {l- [2_ (4_phenoxy_phenyl) _ethylaminemethylamidoethoxy) The same method for phenylpropionic acid (Example 1 'Step 3) was prepared from (2S) _3_ (4_carboxymethoxy_benzyl) _2_methoxy-propionic acid ethyl ^ Preparation 3, step 2) and butyl -(1-phenyl-ethyl) -amine to prepare di- 'to produce gram-free oil. C24H31N05 [M + H] + MS (ES): 414. Example 33 (2S) _3_ {4 _ [(3,3 · Diphenyl-propylaminomethylamidino) -methoxy] -phenyloxo 2-methoxy-propionic acid

85504.doc 200406371 標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4-{1-[2-(4·苯氧基^苯基）-乙基胺甲醯基]-乙氧基}苯基）-丙酸（實 例1、步驟3)之相同方法由（2外3_(4_羧甲氧基_苯基卜2_甲氧 基-丙酸乙酯（製備物3、步驟2)與3,3-二苯基-丙胺製備，以 生產黃色油。C27H29N05 [M+H]+之 MS (ES) : 448。 實例34 (2S)-3-(4-{[卞基_(2_乙氧羰基_乙基胺甲醯基卜甲氧基卜苯 基）^2-甲氧基-丙酸85504.doc 200406371 The title compound is used to prepare (2S, lR) -2-ethoxy-3- (4- {1- [2- (4 · phenoxy ^ phenyl) -ethylamine formamidine Group] -ethoxy} phenyl) -propanoic acid (Example 1, step 3) The same method is described by (2 outer 3_ (4_carboxymethoxy_phenylbu 2_methoxy-propionic acid ethyl ester ( Preparation 3, step 2) was prepared with 3,3-diphenyl-propylamine to produce a yellow oil. MS (ES) of C27H29N05 [M + H] +: 448. Example 34 (2S) -3- (4- {[Fluorenyl_ (2_ethoxycarbonyl_ethylaminemethylmethoxymethylphenylphenyl) ^ 2-methoxy-propionic acid

標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4 [2-(4-苯氧基-苯基）_乙基胺甲醯基]_乙氧基}苯基）_丙酸（實 例1、步驟^之相同方法由（叫3-(4·叛甲氧基-苯基）i甲氧 基_丙酸乙酯飞製備物3、步驟2)與3_苄胺基-丙酸乙酯製備， 以生產供色油。C24H29N07 [M+H]+之 MS (ES) ·· 444 6 實例35 (2S)-2_甲氧基·3_(4_{[3·(甲基-苯基-胺基）_丙基胺甲隨基] 甲氧基}-本基）-丙酸The title compound is used to prepare (2S, 1R) -2-ethoxy-3- (4 [2- (4-phenoxy-phenyl) _ethylaminemethylmethyl] _ethoxy} benzene Group) _propionic acid (Example 1, step ^ The same method was prepared from (called 3- (4 · metamethoxy-phenyl) imethoxy_propionic acid ethyl ester 3, step 2) and 3_ Preparation of benzylamino-ethyl propionate to produce color oil. C24H29N07 [M + H] + MS (ES) · 444 6 Example 35 (2S) -2_methoxy · 3_ (4 _ {[3 · (Methyl-phenyl-amino) -propylaminomethanyl] methoxy} -benzyl) -propionic acid

85504.doc -62- 200406371 標題化/物係經由用以製備（2S，1R)-2-乙氧基-3-(Μ1· [(苯氧基一苯基 &gt; 乙基胺甲醯基卜乙氧基}苯基）_丙酸（實 iJ :驟3)〈相同方法由(2S)_3，_#!甲氧基苯基)-2-甲氧 基丙^乙酿（製備物3、步驟2)與N1-甲基抓苯基.丙m 二胺製備，以；^衾a* 屋辨色油。C22H28N2〇5 [M+H] +之 MS (ES) :401 〇 實例36 (2S)-2_甲氧基_3_(4_{[2_(4_甲氧基·苯氧基）乙基胺甲酸基卜 : 甲氧基}_苯基）-丙酸 。 對掌體85504.doc -62- 200406371 The title / system is used to prepare (2S, 1R) -2-ethoxy-3- (M1 · [(phenoxymonophenyl &gt; ethylaminoformyl) Ethoxy} phenyl) _propionic acid (actual iJ: step 3) <the same method from (2S) _3, _ #! Methoxyphenyl) -2-methoxypropyl ^ ethyl alcohol (preparation 3, Step 2) Preparation of N-methyl phenyl and propyl m diamine with: ^ 衾 a * house discrimination oil. C22H28N2〇5 [M + H] + MS (ES): 401 〇 Example 36 (2S) -2_methoxy_3_ (4 _ {[2_ (4_methoxy · phenoxy) ethylaminocarboxylic acid Gib: methoxy} -phenyl) -propionic acid. Palm body

祛題化$物係經由用以製備（2§，ir)_2_乙氧基 [2-(4_丰氧苯基）·乙基胺甲醯基]-乙氧基}苯基）-丙酸（實 例1、步驟3)之相同方法由US)-3-(4-羧甲氧基-苯基）-2-甲氧 基·丙酸乙酿（製備物3、步騾2)與2-(4-甲氧基-苯氧基）-乙胺 製備’以生產攝色油。C2iH25N07 [M+H]+之MS (ES) : 404。 實例37 (2S)-2-甲氧基_3_{4-[(‘笨氧基_苯基胺甲醯基甲氧基卜苯 基}-丙酸 85504.doc •63- 200406371Elimination of the problem is to prepare (2§, ir) _2_ethoxy [2- (4_fungoxyphenyl) · ethylaminomethylmethyl] -ethoxy} phenyl) -propyl The same method for the acid (Example 1, step 3) was prepared from US) -3- (4-carboxymethoxy-phenyl) -2-methoxypropionic acid (preparation 3, step 2) and 2 -(4-methoxy-phenoxy) -ethylamine preparation 'to produce a color-receptive oil. MS (ES) for C2iH25N07 [M + H] +: 404. Example 37 (2S) -2-methoxy_3_ {4-[('Benoxy_phenylaminomethylmethylmethoxyphenylphenyl) -propionic acid 85504.doc • 63- 200406371

j〇 對掌體 標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4]1一 [2_(4-苯氧基-苯基）_乙基胺甲醯基]_乙氧基丨苯基）_丙酸（實 例1、步騾3)之相同方法、由（2S)_3-(4_羧甲氧基-苯基）_2-肀氧 基_丙酸乙醇i製備物3、步驟2)與各苯氧基-苯胺製備，以生 產無色油。C24'H23N06 [M+H]+之 MS (ES) ·· 421。 實例38 2_甲氧基-3-{3_[(4-苯氧基_苯基胺甲醯基）_甲氧基卜苯基}- 丙酸（異構物1)The title compound of j 用以 palm is used to prepare (2S, lR) -2-ethoxy-3- (4) 1- [2_ (4-phenoxy-phenyl) _ethylaminomethylmethyl ] _Ethoxy 丨 phenyl) _propionic acid (Example 1, step 3) The same method, from (2S) _3- (4_carboxymethoxy-phenyl) _2- methoxy_propionic acid ethanol i Preparation 3, step 2) and each phenoxy-aniline are prepared to produce a colorless oil. C24'H23N06 [M + H] + MS (ES) ·· 421. Example 38 2_methoxy-3- {3 _ [(4-phenoxy_phenylaminemethylamidino) _methoxyphenylphenyl} -propionic acid (isomer 1)

標題化合物係經由用以製備（2S，1R)-2-乙氧基-3-(4-{1-[2-(4-苯氧基-苯基）_乙基胺甲醯基乙氧基丨苯基）_丙酸（實 例1、步驟3)之相同方法由3_(3_羧甲氧基·苯基）-2-甲氧基-丙酸甲酯（製備物4、步驟2)與4-苯氧基·苯胺製備，以生產 無色油。C24H23N06 [M+H]+之MS (ES) : 322。 實例39 (2S&gt;3-{4-[l-(4-第三-丁基·環己基胺甲醯基）-1-甲基-乙氧 85504.doc -64- 200406371 基l·苯基}_2_甲氧基-丙酸 〇The title compound is used to prepare (2S, 1R) -2-ethoxy-3- (4- {1- [2- (4-phenoxy-phenyl) _ethylaminemethylamidoethoxy丨 Phenyl) _propionic acid (Example 1, step 3) The same method is used by 3_ (3_carboxymethoxy · phenyl) -2-methoxy-propionic acid methyl ester (preparation 4, step 2) and Preparation of 4-phenoxy · aniline to produce colorless oil. C24H23N06 [M + H] + MS (ES): 322. Example 39 (2S &gt; 3- {4- [l- (4-Third-butylcyclohexylaminemethylamidino) -1-methyl-ethoxy 85504.doc -64- 200406371 group l · phenyl} _2_methoxy-propionic acid

標題化合物係經由用以製備（2S，1R)-2-乙氧基 [2-(4-苯氧基-苯基）-乙基胺甲醯基 &gt; 乙氧基}苯基丙酸（實 例1、步驟3)之相同方法由（2S)_3_[4_(1_羧基甲基-乙氧基） -* -苯基]-2-甲氧基·丙酸乙酯（製備物5、步驟2)與4_順/反_第三 -丁基-環己胺製備，以生產無色油。C24h37N〇5 [m+H]+之MS (ES) : 420。 實例40 (2S&gt;2-甲氧基甲基-1·[2-(4-苯氧基-苯基）-乙基胺 甲酸基]&quot;乙氧1基}-苯基）-丙酸The title compound is used to prepare (2S, 1R) -2-ethoxy [2- (4-phenoxy-phenyl) -ethylaminomethylamido &gt; ethoxy} phenylpropanoic acid (Example 1. The same method of step 3) consists of (2S) _3_ [4_ (1_carboxymethyl-ethoxy)-* -phenyl] -2-methoxy · propionic acid ethyl ester (Preparation 5, Step 2 ) And 4-cis / trans-tert-butyl-cyclohexylamine to produce a colorless oil. MS (ES) for C24h37NO5 [m + H] +: 420. Example 40 (2S &gt; 2-methoxymethyl-1 · [2- (4-phenoxy-phenyl) -ethylamine formate] &quot; ethoxy 1-yl} -phenyl) -propionic acid

標題化合物係經由用以製備（2S，1R)_2-乙氧基_Μ4_{1_ ； [2β(4_苯氧基·笨基）·乙基胺甲醯基l·乙氧基}苯基）-丙酸（實 例1、步騾3)之相同方法由（2S)-3-[4_(1_羧基_丨_甲基-乙氧基）一 苯基]-2-甲氧基_丙酸乙酯（製備物5、步驟2)與4_苯氧基-苯: 85504.doc -65- 200406371 胺製備，以生產無色油。C28H31N06 [M+H]+之MS (ES) : 478 ‘ ‘- 實例41 (23)-3-(4-{1-[2-(2-乙氧基-苯基）-乙基胺甲酸基]_1-甲基-乙 氧基}-苯基）-2-甲氧基-丙酸 對掌體 ，The title compound is used to prepare (2S, 1R) _2-ethoxy_M4_ {1_; [2β (4_phenoxy · benzyl) · ethylaminomethylmethyl-1-ethoxy} phenyl) -The same method for propionic acid (Example 1, step 3) from (2S) -3- [4_ (1_carboxy_ 丨 _methyl-ethoxy) monophenyl] -2-methoxy_propionic acid Ethyl ester (Preparation 5, Step 2) and 4-phenoxy-benzene: 85504.doc -65- 200406371 amines were prepared to produce a colorless oil. C28H31N06 [M + H] + MS (ES): 478 ''-Example 41 (23) -3- (4- {1- [2- (2-ethoxy-phenyl) -ethylcarbamate ] _1-methyl-ethoxy} -phenyl) -2-methoxy-propionic acid

標題化合i勿係經由用以製備（2S，lR)-2-乙氧基-3-(4-{l- -3 [2-(4-苯氧基-笨基）_乙基胺甲醯基]•乙氧基丨苯基）_丙酸（實 例1、步騾3)之相同方法由（2S)_3-[4-(1_羧基甲基-乙氧基） -苯基]-2-甲氧基-丙酸乙酯（製備物5、步驟2)與2-(2-乙氧基- 苯基）-乙胺製備，以生產無色油。C24H31N06 [M+H] +之MS (ES) : 430。 實例42The title compound i is not used to prepare (2S, lR) -2-ethoxy-3- (4- {l- -3 [2- (4-phenoxy-benzyl) _ethylamine formamidine Group] • ethoxy 丨 phenyl) _propionic acid (Example 1, step 3) The same method is given by (2S) _3- [4- (1_carboxymethyl-ethoxy) -phenyl] -2 -Methoxy-propionic acid ethyl ester (Preparation 5, Step 2) and 2- (2-ethoxy-phenyl) -ethylamine to produce a colorless oil. C24H31N06 [M + H] + MS (ES): 430. Example 42

2-甲氧S-2二甲基_3_(4-{[2_苯氧基_苯基）_乙基胺甲醯基]_ ^ 甲氧基}-苯基）·丙酸2-methoxy S-2 dimethyl_3_ (4-{[2_phenoxy_phenyl) _ethylaminemethylmethyl] _ ^ methoxy} -phenyl) · propionic acid

標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4-{1-[2-(4_苯氧基·笨基）-乙基胺甲醯基]-乙氧基}苯基）-丙酸（實 例卜步騾3)之相同方法由3-(4-羧甲氧基-苯基）-2_甲氧基_2-甲基-丙酸甲酷與2-(4-苯氧基-苯基）-乙胺製備，以生產無色 85504.doc -66- 200406371 油。C27H29 N〇6 [M+H]+之 MS (ES) : 464。 二- 實例43 2-甲氧基-3-(4-{l-甲基-i-[2-(3-三氟甲基·苯基）_乙基胺甲醯 基]-乙氧基}-苯基）-丙酸The title compound is used to prepare (2S, lR) -2-ethoxy-3- (4- {1- [2- (4-phenoxy · benzyl) -ethylaminomethylmethyl] -ethyl The same method of oxy} phenyl) -propionic acid (Example BB3) is obtained from 3- (4-carboxymethoxy-phenyl) -2_methoxy_2-methyl-propionic acid Preparation of 2- (4-phenoxy-phenyl) -ethylamine to produce colorless 85504.doc -66- 200406371 oil. C27H29 No. 6 [M + H] + MS (ES): 464. Bi-Example 43 2-methoxy-3- (4- {l-methyl-i- [2- (3-trifluoromethyl · phenyl) _ethylaminemethylmethyl] -ethoxy} -Phenyl) -propionic acid

標題化合物係經由用以製備（2S，lR)-2-乙氧基_3-(4-{1- [2-(4 -丰氧基__冬基）_乙基胺甲酿基]-乙氧基}苯基）_丙酸（實 -» 例1、步騾3)之相同方法由（2S)-3-[4-(l-羧基小甲基-乙氧基） -苯基]-2-甲氧基-丙酸乙酿（製備物5、步驟2)與2-(3-三氟甲 基-苯基）·乙胺製備，以生產無色油。C23H26F3N05[M-H]-之 MS (ES) : 452。 實例44 (2S)-2-甲氧基_3-{4-[1-甲基-1-(3-三氟甲基-苄基胺甲醯基）_ 乙氧基]-笨基}_丙酸The title compound is used to prepare (2S, lR) -2-ethoxy_3- (4- {1- [2- (4 -fungoxy__winteryl) _ethylaminemethyl]- Ethoxy} phenyl) _propionic acid (actual- »Example 1, step 3) The same method as (2S) -3- [4- (l-carboxy small methyl-ethoxy) -phenyl] 2-Methoxy-propionic acid ethyl alcohol (preparation 5, step 2) and 2- (3-trifluoromethyl-phenyl) · ethylamine were prepared to produce a colorless oil. C23H26F3N05 [M-H] -MS (ES): 452. Example 44 (2S) -2-methoxy_3- {4- [1-methyl-1- (3-trifluoromethyl-benzylaminemethylamidino) _ethoxy] -benzyl} _ Propionic acid

標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4-{1-[2-(4 -苯氧基-苯基）-乙基胺甲酿基]-乙氧基}苯基）_丙酸（實 例1、步騾3)之相同方法由（2S)-3-[4-(l·羧基-1 —甲基-乙氧基） -苯基]-2-甲氧基-丙酸乙酉旨（製備物5、步驟2)與3-三氟甲基-苄胺製備，以生產無色油。C22H24F3N〇5 [M-Η]-之MS (ES)The title compound is used to prepare (2S, lR) -2-ethoxy-3- (4- {1- [2- (4-phenoxy-phenyl) -ethylaminomethyl] -ethyl Oxy} phenyl) _propionic acid (Example 1, step 3) The same method as (2S) -3- [4- (l · carboxy-1 —methyl-ethoxy) -phenyl] -2 -Methoxy-acetic acid propionate (Preparation 5, step 2) and 3-trifluoromethyl-benzylamine to produce a colorless oil. C22H24F3N〇5 [M-Η] -MS (ES)

85504.doc -67- :438 ° 200406371 實例45 (2S)-3-(4_{l_[2-(2-氣基-苯基）_乙基胺甲酸基]_卜甲基_乙 氧基}-笨基&gt;2-甲氧基-丙酸 對掌體85504.doc -67-: 438 ° 200406371 Example 45 (2S) -3- (4_ {l_ [2- (2-Gasyl-phenyl) _ethylcarbamate] _bumethyl_ethoxy} -benzyl &Gt; 2-methoxy-propionic acid palmar body

標題化合物係經由用、以製備（2S，lR)-2-乙氧基-3·(4-{1- [2-(4-苯氧$苯基）_乙基胺甲醯基]_乙氧基丨苯基）·丙酸（實 例1、步驟3)之相同方法由（2S)-3_[仁（1_羧基_丨·甲基·乙氧基） -苯基]-2-甲氧基-丙酸乙酯（製備物5、步驟2)與2_(2_氯基-苯 基）-乙胺製備，以生產無色油。C22H26C1N05 [Μ_ΗΓ之MS (ES) : 420。 實例46 (2S) 3 (4-{1-[(二苯基基甲基）_胺甲醯基]_ι_甲基-乙氧基} _苯基）-2 -甲氧基-丙酸The title compound was used to prepare (2S, 1R) -2-ethoxy-3 · (4- {1- [2- (4-phenoxy $ phenyl) _ethylaminemethylmethyl] _ethyl Oxy 丨 phenyl) · propionic acid (Example 1, step 3) The same method as (2S) -3_ [仁 (1_carboxy_ 丨 · methyl · ethoxy) -phenyl] -2-methoxy Ethyl-propionate (Preparation 5, Step 2) and 2- (2-chloro-phenyl) -ethylamine were prepared to produce a colorless oil. C22H26C1N05 [MS of MS (ES): 420. Example 46 (2S) 3 (4- {1-[(Diphenylylmethyl) _aminomethylmethyl] _ι_methyl-ethoxy} _phenyl) -2 -methoxy-propionic acid

對掌體 祆I化a物係經由用以製備（2S，1R)_2_乙氧基-3-(4-{1_ [2-(心冬乳基-苯基）·乙基胺甲醢基l·乙氧基}苯基）-丙酸（實 例/步驟3)之相同方法由（2S)-3-[4-(l-羧基甲基乙氧基） 苯土] 2甲氧基-丙酸乙酯（製備物5、步驟2)與C-二苯基-3- 基-甲胺製備，以斗丄 ^ 乂 生產揲色油。C27H29N05 [Μ-ΗΓ之 MS (ES) 85504.doc -68 - 200406371 :446 〇 吋2_(2,5-二甲氧基·苯基）-乙基胺甲醯基]-1-甲 基-乙氧基}-苯基）-2-甲氧基-丙酸The pallidium sulfonium a system is used to prepare (2S, 1R) _2_ethoxy-3- (4- {1_ [2- (aspartyl-phenyl) · ethylaminomethylmethyl) l · ethoxy} phenyl) -propionic acid (example / step 3) The same method is used (2S) -3- [4- (l-carboxymethylethoxy) phenyl earth] 2methoxy-propane Ethyl acetate (Preparation 5, Step 2) and C-diphenyl-3-yl-methylamine were prepared to produce ochre oil with 丄 丄 乂. C27H29N05 [MS (ES) of M-ΗΓ 85504.doc -68-200406371: 446 ○ 2_ (2,5-dimethoxy · phenyl) -ethylaminomethylmethyl] -1-methyl-ethyl Oxy} -phenyl) -2-methoxy-propionic acid

0-CK0-CK

松通化合身係經由用以製備（2S，lR)-2_乙氧基_3_(4-{1_ [2-(4_苯氧基-笨基乙基胺甲醯基]-乙氧基}苯基）_丙酸（實 例卜步驟3)之相同方法由（2S)-3-[4-(l-羧基-1-甲基-乙氧基） -苯基]-2-甲氧基-丙酸乙酯（製備物$、步驟2)與2_(2,5_二甲 氧基-苯基）-乙胺製備，以生產無色油。（：2411311^〇7[^1·!^ 之 MS (ES) : 445。 對掌體 實例48Matsudo Chemical Fitting is used to prepare (2S, lR) -2_ethoxy_3_ (4- {1_ [2- (4_phenoxy-benzylethylaminemethylmethyl) -ethoxy} The same method for phenyl) -propionic acid (Example 3, step 3) consists of (2S) -3- [4- (l-carboxy-1-methyl-ethoxy) -phenyl] -2-methoxy- Preparation of ethyl propionate (preparation $, step 2) and 2- (2,5_dimethoxy-phenyl) -ethylamine to produce a colorless oil. (: 2411311 ^ 〇7 [^ 1 ·! ^ Of MS (ES): 445. Example of palm body 48

(2S)-3_(4-{^[2_(2_氟基苯基）_乙基胺甲醯基甲基_乙氧 基}-苯基）-2 -甲氧基-丙酸 對掌體(2S) -3_ (4-{^ [2_ (2_fluorophenyl) _ethylaminomethylmethyl_ethoxy} -phenyl) -2 -methoxy-propionic acid palmar body

標題化合物係經由用以製備（2S，lR)-2_乙氧基-3-(4-{1-[2-(4-苯氧基-苯基）-乙基胺甲醯基]-乙氧基}苯基）_丙酸（實 例1、步騾3)之相同方法由（2S)-3-[4-(l-羧基·1_甲基·乙氧基） -苯基]-2-甲氧基-丙酸乙酯（製備物5、步驟2)與2-(2-氟基-笨 85504.doc -69- 200406371 基）-乙胺製備，以生產無色油。C22H26FN05 [Μ-ΗΓ之MS (ES) :402 。 實例49 (2S)-2-乙氧基_3-(4-{1·甲基·ΐ·[2-(3-三氟甲基-苯基）·乙基 胺甲酿基]•乙氧基}-苯基）_丙酸The title compound is used to prepare (2S, lR) -2-ethoxy-3- (4- {1- [2- (4-phenoxy-phenyl) -ethylaminomethylmethyl] -ethyl Oxy} phenyl) _propionic acid (Example 1, step 3) The same method is given by (2S) -3- [4- (l-carboxy · 1-methyl · ethoxy) -phenyl] -2 -Methoxy-propionic acid ethyl ester (Preparation 5, Step 2) and 2- (2-fluoro-benzyl 85504.doc -69- 200406371) -ethylamine were prepared to produce a colorless oil. C22H26FN05 [MS of MS-ESI (ES): 402. Example 49 (2S) -2-ethoxy_3- (4- {1 · methyl · ΐ · [2- (3-trifluoromethyl-phenyl) · ethylaminomethyl]] ethoxy } -Phenyl) _propionic acid

步驟1 : (2S)-3^[4-(l-第三·丁氧羰基-1-甲基-乙氧基）·苯基] -2-乙氧基-丙酸乙酯Step 1: (2S) -3 ^ [4- (l-Third · butoxycarbonyl-1-methyl-ethoxy) · phenyl] -2-ethoxy-propionic acid ethyl ester

標題化合物係經由用以製備（2S)-3-(4_第三-丁氧羰甲氧 基-苯基）-2-甲氧基-丙酸乙酯（製備物3、步驟1)之相同方法 由（28)-2-乙氣襄-3-(4-經基-苯基）_丙酸乙酉旨（實例251、步驟 3)與2_嗅基-2-甲基-丙酸第三-丁酯製備，以生產黃色油。 C21H32〇6 [Μ+ΗΓ之MS (ES) : 381。 步驟2 : (2S)-3-[4-(l-羧基-1-甲基-乙氧基）-苯基]_2_乙氧基_ 丙酸乙酯The title compound is the same as used to prepare (2S) -3- (4-tert-butoxycarbonylmethoxy-phenyl) -2-methoxy-propionic acid ethyl ester (Preparation 3, Step 1) The method consists of (28) -2-Ethyl-3- (4-acyl-phenyl) -acetic acid propionate (Example 251, step 3) and 2-olyl-2-methyl-propionic acid third -Butyl ester preparation to produce a yellow oil. C21H32〇6 [MS + ES (MS): 381. Step 2: (2S) -3- [4- (l-carboxy-1-methyl-ethoxy) -phenyl] _2_ethoxy_ethyl propionate

-70--70-

85504.doc 200406371 標題化合物係經由用以製備（2S)-3-(4_羧甲氧基_苯基）-2_ 甲氧基-丙酸^乙酯（製備物3、步驟2)之相同方法由（2S)-3-[4-(1-第二丁氧窥基甲基_乙氧基）_苯基]·2_乙氧基，丙酸 乙酯（實例49、步驟1)製備，以生產黃色油。[μ+Η] + 之 MS (ES) : 325。 步騾3 ·· (2S)-2_乙氧基_3-(4-{l-甲基-i-[2-(3-三氟甲基-苯基） -乙基胺甲醯基;μ乙氧基卜苯基）·丙酸85504.doc 200406371 The title compound was prepared via the same method used to prepare (2S) -3- (4_carboxymethoxy_phenyl) -2_methoxy-propionic acid ^ ethyl ester (Preparation 3, Step 2) Prepared from (2S) -3- [4- (1-second butoxylmethyl_ethoxy) _phenyl] · 2-ethoxy, ethyl propionate (Example 49, Step 1), To produce yellow oil. [μ + Η] + MS (ES): 325. Step · 3 · (2S) -2_ethoxy_3- (4- {l-methyl-i- [2- (3-trifluoromethyl-phenyl) -ethylaminomethylmethyl; μethoxybuphenyl) · propionic acid

標題化合物係經由用以製備（2S，1R)-2-乙氧基_3_(4_{1_ [2-(4-苯氧基-苯基）_乙基胺甲醯基卜乙氧基丨苯基广丙酸（實 例1、步騾3)之相同方法由羧基-；u甲基_乙氧基） -苯基]-2-乙氧基-丙酸乙酯（實例49、步驟2)與2_(4_三氟甲基 •苯基）-乙胺製備，以生產無色油。c24H28F3N〇5[M_H]2MS (ES) : 466。 實例50 (2S)-2-乙氧基-3-{4-[l-(3-氟基-5-三氟甲基·苄基胺甲醯基） -1-甲基-乙氧基]•苯基卜丙酸 對掌體The title compound is used to prepare (2S, 1R) -2-ethoxy_3_ (4_ {1_ [2- (4-phenoxy-phenyl) _ethylaminemethylamidobethoxy 丨 benzene The same method as that for propylpropionic acid (Example 1, step 3) was prepared from carboxyl-; umethyl_ethoxy) -phenyl] -2-ethoxy-propionic acid ethyl ester (example 49, step 2) and 2_ (4_trifluoromethyl • phenyl) -ethylamine is prepared to produce a colorless oil. c24H28F3NO5 [M_H] 2MS (ES): 466. Example 50 (2S) -2-ethoxy-3- {4- [l- (3-fluoroyl-5-trifluoromethyl · benzylaminemethylamidino) -1-methyl-ethoxy] • Phenylpropionate on palm body

標題化合物係經由用以製備（2S，1κ)-2_乙氧基_3_(扣{1一The title compound is used to prepare (2S, 1κ) -2_ethoxy_3_ (button {1 一

85504.doc -71- 200406371 [2-(4 -苯氧基-苯基）-乙基胺甲酿基]-乙氧基}苯基）-丙酸（實 例1、步騾3)之湘同方法由（2S)-3-[4-(l-叛基_1_甲基-乙氧基） -苯基]-2-乙氧基-丙酸乙酯（實例49、步驟2)與3-氟基-5-三氟 甲基芊胺製備，以生產無色油。C23H25F4N05 [M-Η]-之MS (ES) : 470。 實例51 (28)-3-(4-{1_[2-(2-氯基-苯基）-乙基胺甲醯基]_1_甲基_乙氧 基}-苯基）_2_乙氧基-丙酸85504.doc -71- 200406371 [2- (4-phenoxy-phenyl) -ethylamine methyl] -ethoxy} phenyl) -propionic acid (Example 1, step 3) The method consisted of (2S) -3- [4- (l-Seryl_1-methyl-ethoxy) -phenyl] -2-ethoxy-propionic acid ethyl ester (Example 49, step 2) and 3 -Preparation of fluoro-5-trifluoromethylphosphonium amine to produce a colorless oil. C23H25F4N05 [M-Η] -MS (ES): 470. Example 51 (28) -3- (4- {1_ [2- (2-chloro-phenyl) -ethylaminomethylmethyl] _1_methyl_ethoxy} -phenyl) _2_ethoxy Propyl-propionic acid

松題化合物係經由用以製備（2S，1R)_2_乙氧基 [2-(4-苯氧基-苯基p乙基胺甲醯基]•乙氧基丨苯基）_丙酸（實The pine title compound is used to prepare (2S, 1R) _2_ethoxy [2- (4-phenoxy-phenyl pethylaminemethylamidino] • ethoxy 丨 phenyl) _propionic acid ( real

例卜步驟3)之相同方法由（2Sm(i-幾基+甲基-乙氧基） -苯基]-2-乙氧基·丙酸乙酯（實例49、步騾2)與2_(2_氯基-苯Example: The same method as in step 3) consists of (2Sm (i-Chloryl + methyl-ethoxy) -phenyl] -2-ethoxy · propionic acid ethyl ester (Example 49, step 2) and 2_ ( 2-chloro-benzene

基）乙胺製=，以生產無色油。CuHmC14N〇5 [m-町之MS (ES) : 434 實例52 (2S)-3-(4-{l_[(二苯基|基甲基胺甲醯基]小甲基_乙氧基}Based) Ethylamine = to produce a colorless oil. CuHmC14N〇5 [m-machi MS (ES): 434 Example 52 (2S) -3- (4- {l _ [(diphenyl | methylmethylaminomethyl)] small methyl_ethoxy}

-苯基-2-乙氧基-丙酸 OH-Phenyl-2-ethoxy-propionic acid OH

85504.doc 72- 200406371 標題化合物係經由用以製備（2S，lR)-2·乙氧基-3-(4-{l- [2-(4_苯氧基^苯基）_乙基胺甲酸基]-乙氧基}苯基）丙酸（實 例1、步驟3)之相同方法由（2S)_3-[4-(l-羧基_1_甲基_乙氧基） -苯基乙氧基-丙酸乙酯（實例49、步驟2)與C-二苯基-3- 基甲胺製備以生產無色油。C28H31N05 [M-Η]-之MS (ES) :462 〇 實例53 (2S) 3 (4 {1 [2_(3_氯基、苯基）_乙基胺甲醯基]小甲基乙氧 -Γ 基卜私基）·2-乙氧基-丙酸85504.doc 72- 200406371 The title compound is used to prepare (2S, lR) -2 · ethoxy-3- (4- {l- [2- (4-phenoxy ^ phenyl) _ethylamine Formate] -ethoxy} phenyl) propionic acid (Example 1, step 3) The same method was used (2S) _3- [4- (l-carboxy_1_methyl_ethoxy) -phenylethyl Ethyloxy-propionate (Example 49, step 2) was prepared with C-diphenyl-3-ylmethylamine to produce a colorless oil. C28H31N05 [M-fluorene] -MS (ES): 462 Example 53 (2S) 3 (4 {1 [2- (3-chloro, phenyl) -ethylaminomethylmethyl]] small methylethoxy- Γ Benzyl) · 2-ethoxy-propionic acid

CI ΟΗCI ΟΗ

r° ch3 標題化/物係經由用以製備⑽，1R)-2-乙氧基-3_(M b [2-(4-冬氧基·苯基）_乙基胺甲酿基]-乙氧基}苯基）_丙酸（實 例1、步驟3) 相商士、、土 士 ,。 冲 ^ 门万法由（2S)_3-[4-(l•羧基_1_甲基-乙氧基） 奉基]2乙1基_丙酸乙酯（實例49、步驟2)與孓氣基_苯 基）-乙胺製備，以生產無色油。C23H28CiN〇5 [圓].之MS (ES) : 434 〇 實例54 ()(U [2-(2,5-二甲氧基_苯基 &gt; 乙基胺甲醯基]·丨_甲 基·乙氧基卜苯基）_2_乙氧基_丙酸 $1¾ 85504.doc 〇 對掌體r ° ch3 The title / system is used to prepare hydrazone, 1R) -2-ethoxy-3_ (M b [2- (4-winteroxy · phenyl) _ethylaminomethyl] -ethyl Oxy} phenyl) _propionic acid (example 1, step 3) Mengwan method consists of (2S) _3- [4- (l • carboxy_1_methyl-ethoxy) fenyl] 2 ethyl 1-yl propionate (Example 49, step 2) and tritium Phenyl) -ethylamine is prepared to produce a colorless oil. MS (ES) for C23H28CiN05 [Circle] .: 434 Example 54 () (U [2- (2,5-dimethoxy_phenyl &gt; ethylaminomethyl)] 丨 methyl · Ethoxybuphenyl) _2_ethoxy_propionic acid $ 1¾ 85504.doc

標題化合物係經由用以製備（2S，lR)-2_乙氧基_3-(4^1β [2-(4-苯氧基-苯基）_乙基胺甲醯基]_乙氧基}苯基）·丙酸（實 例1、步騾3)之相同方法由羧基-丨_甲基-乙氧基） -苯基]-2-乙氧基-丙酸乙\酯（實例49、步騾2)與2_(2,5_二甲氧 基·苯基）-乙、胺製備，以生產無色油。C25h33n〇7[M_H；T之MS (ES) : 458。、 實例55 (2S)-2-乙氧基-3-(4-{l-[2-(2-氟基-苯基）-乙基胺甲醯基]-1- 甲基-乙氧基卜苯基）-丙酸The title compound is used to prepare (2S, lR) -2_ethoxy_3- (4 ^ 1β [2- (4-phenoxy-phenyl) _ethylaminomethylmethyl] _ethoxy } Phenyl) · propionic acid (Example 1, step 3) The same method from carboxy- 丨 _methyl-ethoxy) -phenyl] -2-ethoxy-ethyl propionate (Example 49, Step 骡 2) and 2_ (2,5_dimethoxy · phenyl) -ethyl, amine to produce a colorless oil. C25h33n〇7 [M_H; MS of T (ES): 458. Example 55 (2S) -2-ethoxy-3- (4- {l- [2- (2-fluoro-phenyl) -ethylaminomethylmethyl] -1-methyl-ethoxy Buphenyl) -propionic acid

標題化合、係經由用以製備（2S，lR)-2-乙氧基-3-(4-{l- [2-(4-苯氧基-苯基乙基胺甲醯基]_乙氧基丨苯基）_丙酸（實 例1、步驟3)之相同方法由（2S)_3-[4-( 1-羧基-1-甲基-乙氧基） —苯基乙氧基-丙酸乙酯（實例49、步騾2)與2-(2-氟基-苯 基）_乙胺製備，以生產無色油。C23H28FN05 [Μ-ΗΓ之MS (ES) :416° 實例56 (2S)_3_{3-[U(4_第三-丁基_環己基胺甲醯基）_卜甲基-乙氧 一 85504.doc -74- 基]-苯基卜2-甲氧基-丙酸The title compound is used to prepare (2S, lR) -2-ethoxy-3- (4- {l- [2- (4-phenoxy-phenylethylaminemethylmethyl) _ethoxy Phenyl) _propionic acid (Example 1, step 3) The same method as (2S) _3- [4- (1-carboxy-1-methyl-ethoxy) —phenylethoxy-propionic acid Ethyl ester (Example 49, Step 2) and 2- (2-fluoro-phenyl) -ethylamine were prepared to produce a colorless oil. C23H28FN05 [MS (ES) of M-ΗΓ: 416 ° Example 56 (2S) _3_ {3- [U (4_Third-butyl_cyclohexylaminemethylamidino) _methyl-ethoxy-85504.doc -74-yl] -phenyloxo 2-methoxy-propionic acid

200406371 步驟1 ·· (2S)-3-[3-(l-第三-丁氧羰基-1-甲基·乙氧基）_苯基] -2-甲氧基-丙酸甲酯200406371 Step 1 · (2S) -3- [3- (l-Third-butoxycarbonyl-1-methyl · ethoxy) _phenyl] -2-methoxy-propionic acid methyl ester

標題化合物係經由用以製備（2S)-3_(4-第三-丁氧羰基_甲 氧基-苯基）-2-甲氧基-丙酸乙酯（製備物3、步驟1)之相同方 法由3-(3-經基-苯基）-2-甲氧基-丙酸甲酿（實例9、步驟4)與 2-嗅基-2-甲基·丙酸第三-丁酯製備，以生產黃色油。ih_NMr (CDC13, 200.15 MHz): 07.13-7.09 (m5 1H)，6·84·6·69 (m，3H) 3·95-3·89 (dd，1H，J=6.5，4.4)，3·7 (s，3H)，3.34 (s，3H)5 2·94-2·90 (n^2H)，1.50 (s，6H)，1.43 (s，9H)。 步驟2 : (2S)_3_[3-(1-叛基-1_甲基-乙氧基）·苯基]甲氧基_ 丙酸甲酯The title compound is the same as used to prepare (2S) -3_ (4-Third-butoxycarbonyl_methoxy-phenyl) -2-methoxy-propionic acid ethyl ester (Preparation 3, Step 1) Method: Prepared from 3- (3-Cyclo-phenyl) -2-methoxy-propionic acid methyl ester (Example 9, step 4) and 2-olyl-2-methyl-propionic acid tert-butyl ester To produce yellow oil. ih_NMr (CDC13, 200.15 MHz): 07.13-7.09 (m5 1H), 6.84 · 6 · 69 (m, 3H) 3.95-3 · 89 (dd, 1H, J = 6.5, 4.4), 3.7 (s, 3H), 3.34 (s, 3H) 5 2.94-2.90 (n ^ 2H), 1.50 (s, 6H), 1.43 (s, 9H). Step 2: (2S) _3_ [3- (1-Seryl-1_methyl-ethoxy) · phenyl] methoxy_methyl propionate

標題化合物係經由用以製備（2S)-3-(4-羧甲氧基_苯基）-2-甲氧基-丙酸乙酯（製備物3、步驟2)之相同方法由3-[3-(卜第 85504.doc -75- 200406371 二_丁氧魏基甲基-乙氧基）-苯基]-2-甲氧基-丙酸甲酯（實 例56、步驟1+製備，以生產黃色油。1h_nmr (CDCl3, 2〇〇 15 MHz) . D7.19^7.15 (m, 1H), 6.96-6.79 (m? 3H), 3.96-3.89 (dd, 1H，J一6·5, 4·4)，3·7〇 (s，3H)，3.33 (s，3H)，2.98-2.94 (m，2H)， 1.55 (s，6H) 〇 步風3 · (2S)-3-{3_[l-(4-第三-丁基-環己基胺甲醯基）-1-甲基 -乙氧基]-苯基卜2_甲氧基-丙酸The title compound was prepared from 3- [2] by the same method used to prepare (2S) -3- (4-carboxymethoxy-phenyl) -2-methoxy-propionic acid ethyl ester (Preparation 3, Step 2). 3- (Bus. 85504.doc -75- 200406371 Di-butoxyweilylmethyl-ethoxy) -phenyl] -2-methoxy-propionic acid methyl ester (Example 56, Step 1+ Preparation to produce yellow Oil. 1h_nmr (CDCl3, 200015 MHz). D7.19 ^ 7.15 (m, 1H), 6.96-6.79 (m? 3H), 3.96-3.89 (dd, 1H, J-16.5, 4 · 4 ), 3.70 (s, 3H), 3.33 (s, 3H), 2.98-2.94 (m, 2H), 1.55 (s, 6H) 〇Breeze 3 · (2S) -3- {3_ [l- (4-Third-butyl-cyclohexylaminemethylamidino) -1-methyl-ethoxy] -phenylbenzene 2-methoxy-propionic acid

[2-(4-苯氧基-苯基 &gt; 乙基胺甲醯基]•乙氧基}苯基丙酸（實 標璲化合物係經由用以製備（2S，1R)_2•乙氧 例卜步驟3)之相同方法由（2s)-3外3_(1_羧基_丨·甲基_乙氧基） -苯基]_2_甲氧基_丙酸甲酯（實例％、步騾2)與4_第三順/反_ 丁基·裱己^製備，以生產無色油。C24H37N〇5 [μ-ΗΓ之MS (ES) : 418 〇一 實例57 (2S)-3-(3-{l_[2-(4-乙基·苯基）-乙基胺甲醯基]-；1_甲基_乙氧 基}-苯基_2-甲氧基-丙酸[2- (4-phenoxy-phenyl) ethylaminomethyl] ethoxy} phenylpropanoic acid (actual fluorene compound is used to prepare (2S, 1R) _2 • ethoxy examples The same method as in step 3) consists of (2s) -3 except 3_ (1_carboxy_ 丨 methyl_ethoxy) -phenyl] _2_methoxy_propionic acid methyl ester (example%, step 2 ) And 4_ third cis / trans_butyl · mounting ^ to produce a colorless oil. C24H37N〇5 [μ-ΗΓ 的 MS (ES): 418 〇 Example 57 (2S) -3- (3- {l_ [2- (4-ethyl · phenyl) -ethylaminomethylmethyl]-; 1-methyl_ethoxy} -phenyl_2-methoxy-propionic acid

85504.doc .76- 200406371 標題化合物係經由用以製備（2S，1R)_2_乙氧基_3·(4_^_ [2-(4-苯氧基_笨基）_乙基胺甲醯基]_乙氧基}苯基）_丙酸（實 例丨、步驟3)之相同方法由（2S)-3-[3-(l-羧基-1-甲基-乙氧基） —冬基]甲氧基·丙酸甲酯（實例56、步驟2)與2-(4-乙基-苯 基）-乙胺製備’以生產無色油。C24H31N05 [Μ_ΗΓ之MS (ES) 二 412 ° 實例5885504.doc .76- 200406371 The title compound is used to prepare (2S, 1R) _2_ethoxy_3 · (4 _ ^ _ [2- (4-phenoxy_benzyl) _ethylamine formamidine Group] _ethoxy} phenyl) _propionic acid (Example 丨, step 3) the same method from (2S) -3- [3- (l-carboxy-1-methyl-ethoxy)-winteryl ] Preparation of methyl methoxypropionate (Example 56, step 2) with 2- (4-ethyl-phenyl) -ethylamine 'to produce a colorless oil. C24H31N05 [MS_ES (Μ_ΗΓ) 2 412 ° Example 58

(2S)-2-甲氧基-3_(3-{l-甲基_1-[2_(4_苯氧基-苯基）·乙基胺 _了- 甲酿基]-乙氧基}-苯基-丙酸(2S) -2-Methoxy-3_ (3- {l-methyl_1- [2_ (4_phenoxy-phenyl) · ethylamine_le -methynyl] -ethoxy} -Phenyl-propionic acid

標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4-{1-[2-(4_苯氧笨基）-乙基胺甲醯基l·乙氧基}苯基）-丙酸（實二響 例1、步驟3)1相同方法由（2S)-3-[3-( 1-羧基-1-甲基-乙氧基） β苯基]甲氧基_丙酸甲酯（實例56、步驟2)與4-苯氧基-苯胺 製備’以生產無色油。C28H31N06[M-H]-之MS (ES) : 476。 實例59 3 {3_[1_(3_氟基^-三氟甲基_字基胺甲龜基）_^甲基-乙 氧基]-苯基}-2-甲氧基-丙酸 85504.doc -77- 200406371The title compound is used to prepare (2S, lR) -2-ethoxy-3- (4- {1- [2- (4-phenoxybenzyl) -ethylaminomethylmethyl l-ethoxy } Phenyl) -propionic acid (Example 1, Step 3) 1 In the same way, (2S) -3- [3- (1-carboxy-1-methyl-ethoxy) βphenyl] methoxy Preparation of methyl propionate (Example 56, step 2) with 4-phenoxy-aniline to produce a colorless oil. C28H31N06 [M-H] -MS (ES): 476. Example 59 3 {3_ [1_ (3_Fluoro ^ -trifluoromethyl_famidoamidinyl) _ ^ methyl-ethoxy] -phenyl} -2-methoxy-propionic acid 85504. doc -77- 200406371

才π/匕口物係經由用以製備（2S，lR)-2_乙氧基-3·(4-{1- [2(苯氧基-笨基乙基胺甲酸基]乙氧基》苯基）_丙酸（實 例/、步驟狀相同方法由⑽3·[3仆羧基+甲基-乙氧基） -冬基]:2-甲^基·丙酸甲酿（實例％、步驟2換3-氣基^三氟土 甲基丁胺製成'，以生產無色油。C22H23F4N05 [Μ_ΗΓ之MS (ES) : 456 〇 實例60 (2S) 3 (3_{1_[(二苯基基甲基）_胺甲醯基]_卜甲基_乙氧基} -苯基）_2_甲氧基-丙酸The π / knife system is used to prepare (2S, lR) -2_ethoxy-3 · (4- {1- [2 (phenoxy-benzylethylaminocarboxylate) ethoxy] Phenyl) _propionic acid (example /, step-like method is the same method from ⑽3 · [3 [carboxyl + methyl-ethoxy)-winteryl]: 2-methyl ^ propionic acid methyl alcohol (example%, step 2 Made with 3-air-based trifluoro earth methylbutylamine 'to produce a colorless oil. C22H23F4N05 [MS (ES) of Μ_ΗΓ: 456 〇 Example 60 (2S) 3 (3_ {1 _ [(diphenylmethyl methyl ) _Aminomethyl} -methyl-ethoxy} -phenyl) _2_methoxy-propionic acid

標題化合物係經由用以製備（2S，乙氧基-、(‘{丨-[2-(4-苯氧基-苯基）-乙基胺甲醯基]-乙氧基}苯基）-丙酸（實 : 例1、步騾3)之相同方法由（2S)-3-[3-(l-羧基-1-甲基-乙氧基） -苯基]-2-甲氧基·丙酸甲酯（實例56、步騾2)與C-二苯基-3-基-甲胺製備，以生產無色油。C27H28N05 [M-H]_之MS (ES) 一 85504.doc -78· :446 ° :446 °200406371 二 實例61 (2S)-3-(3-{l-[2♦氯基-苯基&gt; 乙基胺甲酿基甲基-乙氧The title compound was prepared via (2S, ethoxy-, ('{丨-[2- (4-phenoxy-phenyl) -ethylaminomethylmethyl] -ethoxy} phenyl)- The same method for propionic acid (actual: Example 1, step 3) is from (2S) -3- [3- (l-carboxy-1-methyl-ethoxy) -phenyl] -2-methoxy · Preparation of methyl propionate (Example 56, step 2) and C-diphenyl-3-yl-methylamine to produce a colorless oil. C27H28N05 [MH] _MS (ES) 85504.doc -78 ·: 446 °: 446 ° 200 406 371 Two examples 61 (2S) -3- (3- {l- [2 ♦ Chloro-phenyl) Ethylaminomethyl methyl-ethoxy

標題化合物係經由用以製備（2S，1R)_2_乙氧基 基卜苯基-2-甲氧基-丙酸 [2爷苯^二苯基）-乙基胺甲酿基卜乙氧基}苯基）-丙酸（實 例卜步驟3)之相同方法由（2S)-3-〇(l-幾基-i甲基-乙氧基) -苯基]_2_甲氧基_丙酸甲醋（實例％、步驟2)與2々氯基-苯The title compound is used to prepare (2S, 1R) _2_ethoxyphenylphenyl-2-methoxy-propionic acid [2ephenyl ^ diphenyl) -ethylamine methylethoxy } Phenyl) -propionic acid (Example 3, step 3). (2S) -3-〇 (l-Imino-imethyl-ethoxy) -phenyl] _2_methoxy_propionic acid Methyl vinegar (example%, step 2) and 2 chloro-benzene

基）乙胺製備，以生產無色油。C22lI29C1N〇5 之MS (ES) : 418。 實例62 (2S)-2-甲氧基_3_{4_[⑴苯基_乙基胺甲酿基）_甲氧基]-苯釗 •丙酸Base) Ethylamine to produce a colorless oil. MS (ES) for C22lI29C1N05: 418. Example 62 (2S) -2-methoxy_3_ {4_ [⑴phenyl_ethylaminemethyl) _methoxy] -benzine • propionic acid

標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4·{1-[2-(4_苯氧基-苯基）_乙基胺甲醯基]•乙氧基}苯基）-丙酸（實 例1、步驟3)之相同方法由（2S&gt;3♦幾f氧基_苯基）_2甲氧 基丙酸乙醋（製備物3、步驟2)與卜苯基-乙胺製備，以生產 黃色油。C20H23N〇5 [Μ+Hr之MS (ES) : 358。 85504.doc -79- 200406371 實例63 (2S)-3-(3-{n[2-(2,4-二氯基-苯基）_乙基胺甲醯基]-1·甲基_ 乙氧基}-苯基-2-f氧基-丙酸 對掌體The title compound is used to prepare (2S, lR) -2-ethoxy-3- (4 · {1- [2- (4-phenoxy-phenyl) _ethylaminemethylmethyl] • ethyl The same method of oxy} phenyl) -propionic acid (Example 1, step 3) consists of (2S &gt; 3 ♦ several foxy_phenyl) _2 methoxypropionic acid ethyl acetate (preparation 3, step 2) and Preparation of phenyl-ethylamine to produce yellow oil. C20H23NO5 [MS + Hr MS (ES): 358. 85504.doc -79- 200406371 Example 63 (2S) -3- (3- {n [2- (2,4-dichloro-phenyl) _ethylaminomethylmethyl] -1 · methyl_ ethyl Oxy} -phenyl-2-foxy-propionic acid

OHOH

〇 C〇 C

標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4-{1-[2-(4-苯氧憂〜苯基）-乙基胺甲醯基]-乙氧基}苯基）·丙酸（實 例卜步驟3)之鈿同方法由（2S)-3-[3-(l-羧基-1-甲基-乙氧基） -苯基]-2-甲氧基-丙酸甲酯（實例56、步驟2)與2_(2,4-二氯基 -苯基）-乙胺製備，以生產無色油。C22h25C1N05 [M] +之MS (ES) ·· 454, [M+2]+ : 456。 實例64 (2S)-3_(3-{l-[2_(2,6-二氯基-苯基）_乙基胺甲醯基卜卜甲基_ —乙氧基卜苯基-2-甲氧基-丙酸The title compound is used to prepare (2S, 1R) -2-ethoxy-3- (4- {1- [2- (4-phenoxy ~ phenyl) -ethylaminomethylmethyl] -ethyl Oxy} phenyl) · propionic acid (Example 3, step 3): (2S) -3- [3- (l-carboxy-1-methyl-ethoxy) -phenyl] -2- Preparation of methoxy-propionic acid methyl ester (Example 56, step 2) and 2- (2,4-dichloro-phenyl) -ethylamine to produce a colorless oil. MS (ES) of C22h25C1N05 [M] + · 454, [M + 2] +: 456. Example 64 (2S) -3_ (3- {l- [2_ (2,6-dichloro-phenyl) _ethylaminomethylmethylphenylmethyl — ethoxymethylphenyl-2-methoxy -Propionic acid

標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4-{l- ' [2-(4-苯氧基-苯基）_乙基胺甲醯基]•乙氧基}苯基）_丙酸（實 β 例1、步驟3)之相同方法由（2S)_3吋3_(1_羧基甲基_乙氧基）一 85504.doc 200406371 -苯基]-2-甲氧基-丙酸甲酯（實例56、步驟2)與2-(2,6-二氯基 -苯基）-乙胺製-備，以生產無色油。C22h25C1N05 [M] +之MS (ES) : 454, [M+2]+ : 456。 實例65 (2S)-3-[3-(l-庚基胺甲醯基-丨_甲基_乙氧基广苯基]_2-甲氧基 -丙酸 對掌體The title compound is used to prepare (2S, lR) -2-ethoxy-3- (4- {l- '[2- (4-phenoxy-phenyl) _ethylaminemethyl)] Ethoxy} phenyl) _propionic acid (actual β Example 1, step 3) The same method as (2S) _3 inch 3_ (1_carboxymethyl_ethoxy) -85504.doc 200406371 -phenyl]- Prepared from 2-methoxy-propionic acid methyl ester (Example 56, step 2) and 2- (2,6-dichloro-phenyl) -ethylamine to produce a colorless oil. C22h25C1N05 [M] + MS (ES): 454, [M + 2] +: 456. Example 65 (2S) -3- [3- (l-heptylamine formamidine- 丨 _methyl_ethoxyphenyl] _2-methoxy-propionic acid

~'3. 標題化合物喺經由用以製備（2S，1R)_2_乙氧基-3-(4·{1_ [2-(4-苯氧基-苯基）_乙基胺甲醯基卜乙氧基}苯基）_丙酸（實 例1、步驟3)之相同方法由（2S)-3-[3-(l·羧基·ι_甲基-乙氧基） -苯基]-2_甲氧基-丙酸甲酯（實例56、步驟2)與庚胺製備，以 生產無色油。C21H33N〇5 [M+H]+之 MS (ES) : 480。 〇~ '3. The title compound 喺 is used to prepare (2S, 1R) _2_ethoxy-3- (4 · {1_ [2- (4-phenoxy-phenyl) _ethylamine formamidine Ethoxy} phenyl) _propionic acid (Example 1, step 3) The same method as (2S) -3- [3- (l · carboxy · ι_methyl-ethoxy) -phenyl] -2 -Methoxy-propionic acid methyl ester (Example 56, step 2) and heptylamine to produce a colorless oil. C21H33N05 [M + H] + MS (ES): 480. 〇

OH Λ h2c&quot; 實例66OH Λ h2c &quot; Example 66

(2S)_3_(4_{^_[2-(2,4-二氯基-苯基）_乙基胺甲醯基]-卜甲基_ 乙乳基}-苯基）·2-甲氧基-丙酸(2S) _3_ (4 _ {^ _ [2- (2,4-dichloro-phenyl) _ethylaminomethyl} -methyl-ethyl-ethoxy} -phenyl) · 2-methoxy- Propionic acid

標題化合物係經由用以製備（2S，lR)-2_乙氧基_3_(4_{1_ [2_(4·苯氧基-苯基）_乙基胺甲醯基]_乙氧基}苯基）丙酸（實 例1、步驟3)之相同方法由（2S)_3_[4_(1•幾基小甲基·乙氧基) 苯基]-2_甲氧基.丙酸乙醋（製備物5、步觸狀2·(2,4_二氯 51 g 85504.doc -81 - 200406371 基-苯基）-乙胺製備，以生產無g&amp;cC22H25Cl2N05[M_Hr 之 MS (ES) ·· 152, [M+H] : 454。 實例67 (2S)-3-(4-{l-[2-(2,4-二氯基-苯基）_乙基胺甲醯基卜卜甲基^ 乙氧i基}-丰基）-2 ·乙乳基-丙酸The title compound is used to prepare (2S, 1R) -2_ethoxy_3_ (4_ {1_ [2_ (4 · phenoxy-phenyl) _ethylaminemethyl}] _ ethoxy} benzene The same method as that for propanoic acid (Example 1, step 3) was prepared from (2S) _3_ [4_ (1 • kilomethylmethylethoxy) phenyl] -2-methoxy. Ethyl propionate (prepared Material 5. Step-like 2 · (2,4_dichloro 51 g 85504.doc -81-200406371 phenyl-phenyl) -ethylamine preparation to produce g &amp; cC22H25Cl2N05 [M_Hr MS (ES) ·· 152 , [M + H]: 454. Example 67 (2S) -3- (4- {l- [2- (2,4-dichloro-phenyl) -ethylaminomethylformylb-methylmethyl ^ ethoxy i-based} -fungyl) -2 · Ethoxylactyl-propionic acid

標題化合〜物係經由用以製備（2S，1R)_2-乙氧基-3·(4_{1-[2-(4-苯氧基-苯基）_乙基胺甲醯基乙氧基}苯基）_丙酸（實 例1、步驟3)之相同方法由（2S)_3外4_(1_羧基甲基_乙氧基） -苯基]-2-甲氧基-丙酸乙酯（製備物5、步驟2)與2_(2,4_二氯 基&quot;苯基）-乙胺製備，以生產無g&amp;°C22H25Cl2N05[M-H]· 之 MS (ES) ·· 452, [M+H]· : 454。 實例68 (2S) 3-(4_[^[2-(2,6-二氯基-苯基）_乙基胺甲酿基卜卜甲基_ 乙氧基}•苯基）-2-乙氧基-丙酸 nu 對掌體The title compound ~ the system is used to prepare (2S, 1R) _2-ethoxy-3 · (4_ {1- [2- (4-phenoxy-phenyl) _ethylamine methylamidoethoxy } Phenyl) _propionic acid (Example 1, step 3) The same method as (2S) _3 outside 4_ (1_carboxymethyl_ethoxy) -phenyl] -2-methoxy-propionic acid ethyl ester (Preparation 5, step 2) and 2_ (2,4_dichloro group &quot; phenyl) -ethylamine to produce g &amp; ° C22H25Cl2N05 [MH] · MS (ES) ·· 452, [M + H] ·: 454. Example 68 (2S) 3- (4 _ [^ [2- (2,6-dichloro-phenyl) _ethylamine methyl ethyl methyl ethoxy} • phenyl) -2-ethoxy -Propionate nu on palm body

標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4-{l-[2-(4-苯氧基_笨基）_乙基胺甲醯基]•乙氧基}苯基丙酸（實 例1步騍3)之相同方法由（2S)-3-[4-(l-羧基-1-甲基-乙氧基） 85504.doc -82- 200406371 苯基]_2_乙氧基-丙酸乙酯（實例49、步驟2)與2-(2,6-二氯基 •苯基）-乙胺製_備，以生產無色油。c23H27cl2N〇5 [m_h]-之 MS (ES) : 466, [M+H]· : 468。 實例69 (2S)-2_乙氧基·3-(4-{1-[2-(4-乙基-苯基）-乙基胺甲醯基]_1_ 甲基-乙氧基}-苯基）-丙酸The title compound is used to prepare (2S, lR) -2-ethoxy-3- (4- {l- [2- (4-phenoxy_benzyl) _ethylaminomethylmethyl] • ethyl The same method for oxy} phenylpropionic acid (Example 1 step 骒 3) consists of (2S) -3- [4- (l-carboxy-1-methyl-ethoxy) 85504.doc -82- 200406371 phenyl ] _2_Ethoxy-propionic acid ethyl ester (Example 49, step 2) and 2- (2,6-dichloro • phenyl) -ethylamine were prepared to produce a colorless oil. C23H27cl2N〇5 [m_h ] -MS (ES): 466, [M + H] ·: 468. Example 69 (2S) -2-ethoxy · 3- (4- {1- [2- (4-ethyl-phenyl) ) -Ethylaminomethylmethyl] _1_methyl-ethoxy} -phenyl) -propionic acid

標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4-{1-[2-(4-苯氧基-苯基）_乙基胺甲醯基乙氧基丨苯基）_丙酸（實 例1、步驟3)之相同方法由（28)_3-[4_(1-羧基甲基-乙氧基） -苯基]-2-乙氧基-丙酸乙酯（實例49、步騾2)與2-(4-乙基-苯 基）·乙胺製備，以生產無色油。C25H33N05 [M+H]+之MS (ES) :428 ° 實例70 (2S)-2 -乙乳基- 3-(4-{l_[2-(2 -乙氧基-苯基）-乙基胺甲酸基] _1_甲基-乙氧基}-苯基）-丙酸 對掌體The title compound is used to prepare (2S, lR) -2-ethoxy-3- (4- {1- [2- (4-phenoxy-phenyl) _ethylaminemethylamidoethoxy丨 Phenyl) _propionic acid (Example 1, step 3) The same method is given by (28) _3- [4_ (1-carboxymethyl-ethoxy) -phenyl] -2-ethoxy-propionic acid ethyl An ester (Example 49, Step 2) was prepared with 2- (4-ethyl-phenyl) · ethylamine to produce a colorless oil. C25H33N05 [M + H] + MS (ES): 428 ° Example 70 (2S) -2 -Ethyl-3- (4- {l_ [2- (2-ethoxy-phenyl) -ethyl Carbamate] _1_methyl-ethoxy} -phenyl) -propionic acid

85504.doc -83- 200406371 標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4_{l-[2-(4-禾氧基二笨基）_乙基胺甲縫基]•乙氧基}苯基）_丙酸（實 例1、步驟3)之相同方法由（2幻-3-[4-(1-羧基-1_甲基-乙氧基） -本基]-2-乙氧基-丙酸乙酉旨（實例49、步驟2)與2-(2-乙氧基- 苯基）_乙胺製備，以生產無色油。CmH^NO6 [M+H] +之MS (ES) : 444。 實例71 (2S)-2-乙氧基_3-[4-(1_虔基胺甲醯基-1_甲基-乙氧基）-苯基] : -丙酸85504.doc -83- 200406371 The title compound is used to prepare (2S, lR) -2-ethoxy-3- (4_ {l- [2- (4-oxaoxydibenzyl) _ethylamine Methanoyl] • ethoxy} phenyl) _propionic acid (Example 1, step 3) The same method is given by (22-3- [4- (1-carboxy-1_methyl-ethoxy)- Benzoyl] -2-ethoxy-propionic acid ethyl ester (Example 49, step 2) and 2- (2-ethoxy-phenyl) _ethylamine were prepared to produce a colorless oil. CmH ^ NO6 [M + MS (ES) of H] +: 444. Example 71 (2S) -2-ethoxy_3- [4- (1-pyridylaminomethylamido-1_methyl-ethoxy) -phenyl ]: -Propionic acid

對掌體 標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4-{1-[2-(4-苯氧基-苯基）_乙基胺甲醯基]_乙氧基}苯基兴丙酸（實 例1、步騾30相同方法由（2S)-3-[4-(l-羧基-1-甲基-乙氧基） -苯基]-2-乙氧基-丙酸乙酯（實例49、步騾2)與庚胺製備，以 生產無色油。C22H33N05 [M+H]+之MS (ES) : 394。 實例72 (11，3)-3-[4-(1-爷氧羰基-乙氧基）-苯基]_2-乙氧基-丙酸乙酯 將三苯膦（1.66克、6.34毫莫耳）添加入2-(S)-羥基-丙酸苄 酯（0.966克、5·36毫莫耳）與（s)-2-乙氧基_3-(4-羥基-苯基）-丙酸乙酯（1.16克、4.88毫莫耳）之THF溶液（30毫升）。令該混 合物冷卻至0°C，並以5分鐘時間逐滴添加DIAD(偶氮二羧酸 85504.doc -84- 200406371 二異丙酯）（1.18克、5.86毫莫耳）。令混合物於回溫至室溫之 同時攪拌18小時。以水（2毫升）止熱反應，並濃縮成殘渣， 利用含20% EtOAc/己烷之矽膠層析純化，以提供產物（1.05 克、49%)並回收起始材料（（S)-2-乙氧基-3-(4-羥基-苯基）-丙 酸乙酯（0.31克）。The title compound of palmar is used to prepare (2S, 1R) -2-ethoxy-3- (4- {1- [2- (4-phenoxy-phenyl) _ethylaminomethylmethyl) ] _Ethoxy} phenylpropanoic acid (Example 1, step 骡 30 from (2S) -3- [4- (l-carboxy-1-methyl-ethoxy) -phenyl] -2 -Ethoxy-ethyl propionate (Example 49, Step 2) and heptylamine to produce a colorless oil. MS (ES) of C22H33N05 [M + H] +: 394. Example 72 (11,3)- 3- [4- (1-Ethoxycarbonyl-ethoxy) -phenyl] -2-ethoxy-propionic acid ethyl ester Add triphenylphosphine (1.66 g, 6.34 mmol) to 2- (S) -Benzyl hydroxy-propionate (0.966 g, 5.36 mmol) and (s) -2-ethoxy-3- (4-hydroxy-phenyl) -ethyl propionate (1.16 g, 4.88 mmol) Mol) in THF solution (30 ml). The mixture was cooled to 0 ° C, and DIAD (azodicarboxylic acid 85504.doc -84- 200406371 diisopropyl ester) (1.18 g) was added dropwise over 5 minutes. , 5.86 mmol). Allow the mixture to stir for 18 hours while warming to room temperature. The reaction was stopped with water (2 ml) and concentrated to a residue, which was purified by silica gel chromatography containing 20% EtOAc / hexane. To provide products 1.05 g, 49%) and recovered starting material ((S) -2- ethoxy-3- (4-hydroxy - phenyl) - propionic acid ethyl ester (0.31 g).

(R，S)-3-[4-(l-羧基·乙氧基）-苯基]-2-乙氧基-丙酸乙酯(R, S) -3- [4- (l-carboxy · ethoxy) -phenyl] -2-ethoxy-propionic acid ethyl ester

將Pd-C (5%、100毫克）之EtOH (10毫升）泥漿加入溶於 EtOH (20毫升）與Η20 (0.5毫升）之（R，S)-3-[4-(l_苄氧羰基-乙 氧基）-苯基]T2-乙氧基-丙酸乙酯（1.05克、2.63毫莫耳）溶液 。令懸浮液於氣球壓:力（balloon pressure)下氫化2小時。令 該混合物濾過矽膠片，並濃縮成殘渣；然後，利用含EtOAc/ 己烷（25%至100%)之矽膠層析純化，以提供酸產物（550毫克 、68%)。 85504.doc -85- 200406371Pd-C (5%, 100 mg) in EtOH (10 ml) was added to (R, S) -3- [4- (l_benzyloxycarbonyl) dissolved in EtOH (20 ml) and Η20 (0.5 ml). -Ethoxy) -phenyl] T2-ethoxy-propionic acid ethyl ester (1.05 g, 2.63 mmol) solution. The suspension was hydrogenated under balloon pressure for 2 hours. The mixture was filtered through a piece of silica gel and concentrated to a residue; then, it was purified by silica gel chromatography containing EtOAc / hexane (25% to 100%) to provide the acid product (550 mg, 68%). 85504.doc -85- 200406371

NaOHNaOH

(!^，3)-3-(4-{1-[2-(3-氣基-苯基）-乙基胺甲醯基]-乙氧基}-苯 基）-2 -乙乳基-丙酸 令（R，S)-3-[4-(l -棱基-乙氧基）-苯基]_2_乙氧基-丙酸乙酉旨 (310毫克、1.00毫莫耳）之0120：12(35毫升）溶液經01^八？（207 毫克、1.70毫莫耳）與EDC (286毫克、1.50毫莫耳）處理。令 該混合物於室溫攪拌10分鐘，然後經3-氯苯基乙胺（201毫克 、1.3毫莫0處-理。令該反應混合物攪拌2小時，並經NH4C1 (水溶液）止熱、以CH2C12 (2X35毫升）萃取，並經NhS04脫 水，利用含EtOAc/己烷（20-35%)之矽膠管柱純化，以產生 中間體酯產物（291毫克、65%)。 然後，溶該乙基酯於甲醇（2.0毫升）與THF (1.0毫升），並 以NaOH (2.0當量濃度、3.0毫升）處理該溶液。令該反應混 合物於室溫攪拌18小時，以HC1 (1.0當量濃度、6.0毫升）中 和至pH=7並濃縮。經EtOAc (3 X 20·毫升）萃取、通過Na2S04 脫水，利用含EtOAc/己烷（35%-100%)與 MeOH/EtOAc (5%) 85504.doc -86- 200406371 之矽膠管柱純化，以產生終酸產物（130毫克、兩個步驟總 和為29%)。二(! ^, 3) -3- (4- {1- [2- (3-Gasyl-phenyl) -ethylaminemethyl] -ethoxy} -phenyl) -2 -ethoxylactyl -Propionic acid order (R, S) -3- [4- (l-radyl-ethoxy) -phenyl] _2_ethoxy-propionic acid ethyl ester (310 mg, 1.00 mmol) : 12 (35 ml) solution after 01 ^ 8? (207 mg, 1.70 mmol) and EDC (286 mg, 1.50 mmol). The mixture was allowed to stir at room temperature for 10 minutes, and then treated with 3-chlorophenylethylamine (201 mg, 1.3 mmol). The reaction mixture was allowed to stir for 2 hours, and heat-shielded with NH4C1 (aqueous solution), and CH2C12 (2X35 ml) was extracted and dehydrated with NhS04, and purified using a silica gel column containing EtOAc / hexane (20-35%) to give an intermediate ester product (291 mg, 65%). Then, the ethyl ester was dissolved The solution was treated in methanol (2.0 mL) and THF (1.0 mL) and treated with NaOH (2.0 equivalent concentration, 3.0 mL). The reaction mixture was stirred at room temperature for 18 hours in HC1 (1.0 equivalent concentration, 6.0 mL) And to pH = 7 and concentrated. Extracted with EtOAc (3 X 20 · mL), dehydrated over Na2S04, using EtOAc / hexane (35% -100%) and MeOH / EtOAc (5%) 85504.doc -86- 200406371 was purified on a silica gel column to produce the final acid product (130 mg, 29% in two steps).

(8,3)-3-[4-(1-第三-丁氧羧基-乙氧基）_苯基]-2-乙氧基-丙酸 乙酯 一 將三苯膦（2·~21克、8.44毫莫耳）添加入2_(R)_羥基丙酸第 三_丁酯（1.23克、8.44毫莫耳）與(S)-2_乙氧基-3-(4_羥基·苯 基）-丙酸乙酯（2.01克、8.44毫莫耳）之THF溶液（100毫升）。 令該混合物冷卻至〇°C，並以5分鐘時間逐滴添加DIAD (偶 氮二羧酸二異丙酯）（1.70克、8.44毫莫耳）。令混合物於回溫 至室溫之同時攪拌18小時。以水（2毫升）止熱反應、並濃縮 成殘渣，利用含20% EtOAc/己烷之矽膠層析純化，以提供 產物（0.99克二12%)並回收起始材料（(S)-2-乙氧基-3-(4-羥基 苯基）-丙fet乙酉旨（0.85克）。 實例74(8,3) -3- [4- (1-Third-butoxycarboxy-ethoxy) _phenyl] -2-ethoxy-propionic acid ethyl ester triphenylphosphine (2 · ~ 21 G, 8.44 millimoles) added 2_ (R) _hydroxypropionic acid third-butyl ester (1.23 grams, 8.44 millimoles) and (S) -2_ethoxy-3- (4_hydroxy · benzene ) -Ethyl propionate (2.01 g, 8.44 mmol) in THF (100 ml). The mixture was allowed to cool to 0 ° C, and DIAD (diisopropyl azodicarboxylate) (1.70 g, 8.44 mmol) was added dropwise over 5 minutes. The mixture was allowed to stir for 18 hours while warming to room temperature. The reaction was quenched with water (2 ml) and concentrated to a residue, which was purified by silica gel chromatography with 20% EtOAc / hexanes to provide the product (0.99 g-12%) and recover the starting material ((S) -2 -Ethoxy-3- (4-hydroxyphenyl) -propetyl acetate (0.85 g). Example 74

-87· 85504.doc 200406371 (S，S)-3-[4-(l-羧基-乙氧基）-笨基]-2-乙氧基-丙酸乙酯 令（S，S)-3-t^(l-第三-丁氧羰基-乙氧基苯基]_2-乙氧基-丙酸乙酯（1.10克、3.00毫莫耳）之CH2C12 (5.0毫升）與TFA (4.0毫升）與水（0.2毫升）溶液攪拌12小時。令該混合物濃縮 至殘渣，並利用含EtOAc/己烷（50%)之矽膠層析純化，以提 供酸產物（0.91克、98%)。-87 · 85504.doc 200406371 (S, S) -3- [4- (l-carboxy-ethoxy) -benzyl] -2-ethoxy-propionic acid ethyl ester (S, S) -3 -t ^ (l-Third-butoxycarbonyl-ethoxyphenyl) _2-ethoxy-propionic acid ethyl ester (1.10 g, 3.00 mmol) CH2C12 (5.0 ml) and TFA (4.0 ml) Stir with a solution of water (0.2 mL) for 12 hours. The mixture was concentrated to a residue and purified using silica gel chromatography containing EtOAc / hexane (50%) to provide the acid product (0.91 g, 98%).

實例74A (S，S)-3-(4_il-[2-(2•氣基-苯基）-乙基胺甲醯基]-乙氧基卜苯 基）-2-乙氧基-丙酸 令（8,8)-3-[4-(1-叛基-乙氧基）-苯基]-2-乙氧基-丙酸乙酯 (46.5¾ 克、0.150¾ 莫耳）之 CH2C12(2 毫升）溶液經 DMAP(27 毫克、0.225毫莫耳）與EDC (43毫克、0.225毫莫耳）處理。令 該混合物於室溫攪拌10分鐘，然後經2-氣苯基乙胺（47毫克 、0.300¾莫耳）處理。令該反應混合物揽拌2小時，並經nh4C1 (水溶液）止熱、以CH2Ch(2X5毫升）萃取，並經Na2S04脫水 ’利用含EtOAc/己燒（25%)之石夕膠管拄純化，以產生中間體 85504.doc -88- 200406371 酉旨產物。 然後，溶諸乙基酯於甲醇（0.5毫升）與THF(0 25毫升），並 以Na〇H (2.〇當量濃度、G.5毫升）處理該溶液。令該反應混 合物於室溫攪拌18小時，以HC1 (1.〇當量濃度、1〇毫升）中 和至PH=7並濃縮。經Et0Ae (3 χ 2毫升）萃取、通過Na2s〇4 脫水，利用含£扣八〇/己烷（35%_1〇〇%)與]^〇11/玢〇心（5%) 之矽膠管柱純化，以產生終酸產物（23毫克、兩個步驟總和 為37%)〇 \ &quot; 2乙氧基[1-(3-二氟甲基_苯乙基胺甲疏基）·乙氧基]_ 苯基卜丙酸、，〜 ^-NMRC^OMHz, CDC13)： D1.07 (br s5 3H), 1.46 (d, 3H? J=6.8Hz)? 2.80-3.01 (m? 4H), 3.28-3.32 (m? 1H)? 3.48-3.58 (m? 3H)5 3.88 (br s5 1H)5 4.58 (q? 1H? J=6.4 Hz)5 6.57-6.71 (m? 1H)，6·73 (d，2H，J=7.8 Hz)，6.98-7.18 (m，5H)，7.28 (d，1H， J=7.8 Hz)。 MS (MH+) ： 420.2Example 74A (S, S) -3- (4-il- [2- (2 • Gas-phenyl) -ethylaminomethyl] -ethoxybuphenyl) -2-ethoxy-propionic acid Let (8,8) -3- [4- (1-tertyl-ethoxy) -phenyl] -2-ethoxy-propionic acid ethyl ester (46.5¾ g, 0.150¾ mole) CH2C12 ( 2 ml) solution was treated with DMAP (27 mg, 0.225 mmol) and EDC (43 mg, 0.225 mmol). The mixture was allowed to stir at room temperature for 10 minutes, and then treated with 2-phenylethylamine (47 mg, 0.300¾ mole). The reaction mixture was allowed to stir for 2 hours, and was heat-shielded with nh4C1 (aqueous solution), extracted with CH2Ch (2X5 ml), and dehydrated with Na2S04, and purified using a Shixi gel tube containing EtOAc / hexane (25%) to produce Intermediate 85504.doc -88- 200406371 Diminished product. Then, the ethyl esters were dissolved in methanol (0.5 ml) and THF (0 25 ml), and the solution was treated with NaOH (2.0 equivalents, G.5 ml). The reaction mixture was stirred at room temperature for 18 hours, neutralized with HC1 (1.0 equivalent concentration, 10 ml) to pH = 7 and concentrated. Extracted with Et0Ae (3 x 2 ml), dehydrated with Na2s〇4, using a silica gel column containing £ 80 / hexane (35% -100%) and ^ 〇11 / 玢 〇 心 (5%) Purified to produce the final acid product (23 mg, 37% in two steps) 2 &quot; 2 ethoxy [1- (3-difluoromethyl_phenethylamine methylsulfanyl) · ethoxy ] _ Phenylpropionic acid, ~~ -NMRC ^ OMHz, CDC13): D1.07 (br s5 3H), 1.46 (d, 3H? J = 6.8Hz)? 2.80-3.01 (m? 4H), 3.28 -3.32 (m? 1H)? 3.48-3.58 (m? 3H) 5 3.88 (br s5 1H) 5 4.58 (q? 1H? J = 6.4 Hz) 5 6.57-6.71 (m? 1H), 6.73 (d , 2H, J = 7.8 Hz), 6.98-7.18 (m, 5H), 7.28 (d, 1H, J = 7.8 Hz). MS (MH +): 420.2

實例75 2-乙氧基-3_[4-(l-己基胺甲醯基-乙氧基）_苯基]_丙酸 標題化合物係利用製備（&amp;8)_3_(4-{1-[2-(2-氯基-笨基）_ 乙基胺甲醯基]-乙氧基卜苯基）_2_乙氧基-丙酸之相同方法 製成。iH-NMR (4〇〇 MHz，CDC13) : 口0.84 (t，3H，J=6.8 Hz)， 85504.doc -89- 200406371 1.17 (t，3H，J=6.7 Hz)，1.22-1.27 (m，8H)，1·44 (t，2H，J=6.8 Hz)，1.54 (d，&quot;3H，J=6.8 Hz)，2.93-2.98(dd，1H，J=7.3 Hz，13.7 Hz)，3.04-3.08 (dd，1H，J=4.2 Hz，14.3 Hz)，3.41-3.46 (m， 1H)，3.58-3.64 (m，1H)，4.03 (dd，1H，J=4.4 Hz，7.8 Hz)，4.64 (q，1H，J=6.8 Hz)，6.46 (t，1H，J=5.4 Hz)，6·82 (d，2H，J=8.3Example 75 2-ethoxy-3_ [4- (l-hexylaminemethylamidino-ethoxy) _phenyl] _propionic acid The title compound was prepared using &amp; 8) _3_ (4- {1- [ 2- (2-Chloro-benzyl) -ethylaminomethyl] -ethoxyphenyl) -2-ethoxy-propionic acid is prepared in the same manner. iH-NMR (400 MHz, CDC13): 0.84 (t, 3H, J = 6.8 Hz), 85504.doc -89- 200406371 1.17 (t, 3H, J = 6.7 Hz), 1.22-1.27 (m, 8H), 1.44 (t, 2H, J = 6.8 Hz), 1.54 (d, &quot; 3H, J = 6.8 Hz), 2.93-2.98 (dd, 1H, J = 7.3 Hz, 13.7 Hz), 3.04- 3.08 (dd, 1H, J = 4.2 Hz, 14.3 Hz), 3.41-3.46 (m, 1H), 3.58-3.64 (m, 1H), 4.03 (dd, 1H, J = 4.4 Hz, 7.8 Hz), 4.64 ( q, 1H, J = 6.8 Hz), 6.46 (t, 1H, J = 5.4 Hz), 6.82 (d, 2H, J = 8.3

Hz)，7.18 (d，2H，J=8.8 Hz)。 MS (MH+) ： 366.2Hz), 7.18 (d, 2H, J = 8.8 Hz). MS (MH +): 366.2

實例76 3-三-丁基-環己基胺曱醯基）-乙氧基]•苯基})-2_ 乙氧基-丙酸 標題化合物係經由製備（8,8)-3-(4-{1-[2-(2_氯基_笨美） 乙基胺甲Si基]-乙氧基}苯基）-2·乙氧基-丙酸之相ρη、 曰Η万法製 成。1H-NMR(400 MHz，CDC13，主要異構物）：□〇 81 (祀) 0.88-0.98 (m，3H)，1.05-1.17 (m，6H)，1.51(d，3H τ 5 J^6.8 Hz) 1.70-1.88 (m，3H)，1.98-2.01 (m，1H)，2·84_2·90 ,Example 76 3-tri-butyl-cyclohexylaminofluorenyl) -ethoxy] • phenyl})-2_ethoxy-propionic acid The title compound was prepared via (8,8) -3- (4- {1- [2- (2_Chloro_Benmei) ethylaminomethylSi group] -ethoxy} phenyl) -2 · ethoxy-propionic acid phase ρη, said Η method. 1H-NMR (400 MHz, CDC13, major isomers): 〇81 (sacrifice) 0.88-0.98 (m, 3H), 1.05-1.17 (m, 6H), 1.51 (d, 3H τ 5 J ^ 6.8 Hz ) 1.70-1.88 (m, 3H), 1.98-2.01 (m, 1H), 2.84_2 · 90,

(dd，1H J=7.3 Hz，13·7 Hz)，2.99.3.04 (dd，1H，J=4.2 】 ，14.3 Hz) 3·31 (br s，1H)，3·54·3·57 (m，1H)，3.64-3.72 (m， 3.95 (b -90- 85504.doc 200406371 s，1Η)，4·60 (q，1H，J=6.8 Hz)，6.27 (d，1H，J=8.3 Hz)，6.82 (d， 2H，J=8.3 Hz)，7·18 (d，2H，J=7.8 Hz)。 MS(MH+) : 420.3(dd, 1H J = 7.3 Hz, 13.7 Hz), 2.99.3.04 (dd, 1H, J = 4.2), 14.3 Hz) 3.31 (br s, 1H), 3.54 · 3 · 57 (m , 1H), 3.64-3.72 (m, 3.95 (b -90- 85504.doc 200406371 s, 1Η), 4.60 (q, 1H, J = 6.8 Hz), 6.27 (d, 1H, J = 8.3 Hz) , 6.82 (d, 2H, J = 8.3 Hz), 7.18 (d, 2H, J = 7.8 Hz) MS (MH +): 420.3

2-乙氧基-3^44-1^(3-三氟甲基-芊基胺甲醯基）-乙氧基]-苯二 基}-丙酸 標題化合物係利用製備（S，S)_3_(4-{l-[2-(2-氯基-苯基）-乙基胺甲醯基l·乙氧基}-苯基）-2-乙氧基-丙酸之相同方法 製成。iH-NMR (400MHz，CDC13) : 口1.07 (t，3H，J=6.7 Hz)，2-ethoxy-3 ^ 44-1 ^ (3-trifluoromethyl-fluorenylaminomethylmethyl) -ethoxy] -benzenediyl} -propionic acid The title compound was prepared using (S, S) _3_ (4- {l- [2- (2-Chloro-phenyl) -ethylaminomethylmethyl-1-ethoxy} -phenyl) -2-ethoxy-propionic acid . iH-NMR (400MHz, CDC13): 1.07 (t, 3H, J = 6.7 Hz),

1.52 (d，3H，J=6.8 Hz)，2·82-2·89 (dd，1H，J=7.3 Hz, 13.7 Hz)， 2.95-3.02 (dd，1H，J=4.2 Hz，14.3 Hz)，3.27-3.30 (m，1H)， 3.50-3.54 (巧 1H)，3·92 (dd，1H，J=4.4 Hz，7.8 Hz)，4.47 (d， 2H，J=5.9 Hz)，4.64 (q，2H，J=7.3 Hz), 6.76 (d，2H，J=7.3 Hz)， 6.06-7.14 (m，3H)，7.32-7.46 (m，4H); MS (MH+) : 440.2。1.52 (d, 3H, J = 6.8 Hz), 2.82-2 · 89 (dd, 1H, J = 7.3 Hz, 13.7 Hz), 2.95-3.02 (dd, 1H, J = 4.2 Hz, 14.3 Hz), 3.27-3.30 (m, 1H), 3.50-3.54 (1H), 3.92 (dd, 1H, J = 4.4 Hz, 7.8 Hz), 4.47 (d, 2H, J = 5.9 Hz), 4.64 (q, 2H, J = 7.3 Hz), 6.76 (d, 2H, J = 7.3 Hz), 6.06-7.14 (m, 3H), 7.32-7.46 (m, 4H); MS (MH +): 440.2.

實例78 2 -乙氧基-3-{4-[l-(5 -氣基-3-二氣甲基基胺甲驢基）-乙氧 85504.doc -91 - 200406371 基]-苯基}-丙酸 標題化合勒係利用製備（8,8)-3-(4-{1-[2-(2-氯基-苯基）-乙基胺甲酸基]-乙氧基}-苯基）-2·乙氧基-丙酸之相同方法 製成。iH-NMR (400 MHz，CDC13) ·· 口1.07 (t，3H, J=6.7 Hz)， 1·53 (d，3H，J=6.8 Hz)，2.82-2.89 (dd，1H，J=7.3Hz，13.7 Hz)， 2.95-3.02 (dd，1H，J=4.2 Hz，14.3 Hz)，3.27-3.35 (m，1H)， 3.53-3.58 (m，1H)，3.93 (dd，1H，J=4.4 Hz，7.8 Hz)，4.40-4.50 (m，2H)，4.62 (q，1H，J=6.8 Hz)，6.76 (d，2H，J=7.3 Hz)，7·00 (d，1H，J=8.8一Hz)，7.13-7.20 (m，5H); MS (MH+) : 486·1。Example 78 2 -Ethoxy-3- {4- [l- (5-Gas-3-diaminomethylaminomethyldonyl) -ethoxy 85504.doc -91-200406371 radical] -phenyl} -Propionic acid title compound is prepared using (8,8) -3- (4- {1- [2- (2-chloro-phenyl) -ethylcarbamate] -ethoxy} -phenyl ) -2 · Ethoxy-propionic acid is prepared in the same way. iH-NMR (400 MHz, CDC13) ·· 1.07 (t, 3H, J = 6.7 Hz), 1.53 (d, 3H, J = 6.8 Hz), 2.82-2.89 (dd, 1H, J = 7.3Hz , 13.7 Hz), 2.95-3.02 (dd, 1H, J = 4.2 Hz, 14.3 Hz), 3.27-3.35 (m, 1H), 3.53-3.58 (m, 1H), 3.93 (dd, 1H, J = 4.4 Hz , 7.8 Hz), 4.40-4.50 (m, 2H), 4.62 (q, 1H, J = 6.8 Hz), 6.76 (d, 2H, J = 7.3 Hz), 7.00 (d, 1H, J = 8.8 a Hz), 7.13-7.20 (m, 5H); MS (MH +): 486.1.

2_乙$基-3-{4-[1-(3-苯基-芊基胺甲醯基）·乙氧基]-苯基}_ 丙酸 π 乂化合H系利用製備（s，s)_3-(4-{1_[2_(入氯基·苯基兴 乙基&amp;甲聽基]·乙氧基卜苯基）-2-乙氧基-丙酸之相同方法 製成。4 ΤνΤΑ/ττ^ U_NMR (400 MHz，CDC13) : 口1.02 (t，3Η，J=6.7 Ηζ)， 1,52 (d，3li，J=6.8 Hz)，2.78-2.84 (dd，1H，J=7.3 Hz，13·7 Hz)， 2.95-3 〇o /., ·υζ (dd，1H，J=4.2 Hz，14·3 Hz)，3.22-3.27 (m，1H)， 3·48&quot;3·52 (m9 1H)9 3.89 (dd? 1H5 J=4A Hz? 7.8 Hz), 4.40-4.50 3H)，6·75 (d，2H，J=7.3 Hz)，7.00 (br s，1H)，7·10 (d，2H， j = 7.8 Hy\ n 1Z)，7.28-7.49 (m，9H); MS (MH+) : 448.2。 85504.doc -92- 2004063712-Ethyl-3- {4- [1- (3-phenyl-fluorenylaminomethylamidino) · ethoxy] -phenyl} _propionic acid, π, hydrazone compound H is prepared using (s, s ) _3- (4- {1_ [2_ (Chloro-phenylphenylethyl &amp; methenyl] -ethoxyphenylphenyl) -2-ethoxy-propionic acid is prepared by the same method. 4 ΤνΤΑ / ττ ^ U_NMR (400 MHz, CDC13): 1.02 (t, 3Η, J = 6.7 Ηζ), 1,52 (d, 3li, J = 6.8 Hz), 2.78-2.84 (dd, 1H, J = 7.3 Hz, 13.7 Hz), 2.95-3 〇o /., · Υζ (dd, 1H, J = 4.2 Hz, 14.3 Hz), 3.22-3.27 (m, 1H), 3.48 &quot; 3.52 (m9 1H) 9 3.89 (dd? 1H5 J = 4A Hz? 7.8 Hz), 4.40-4.50 3H), 6.75 (d, 2H, J = 7.3 Hz), 7.00 (br s, 1H), 7.10 (d, 2H, j = 7.8 Hy \ n 1Z), 7.28-7.49 (m, 9H); MS (MH +): 448.2. 85504.doc -92- 200406371

實例80 2-乙氧基-3-{4-[l-(4-苯氧基-苯基乙基胺甲醯基）-乙氧基]- 苯基}_丙酸 標題化合物係利用皱備（S，S)-3-(4·{M2-(2-氯基-苯基）-乙基胺甲酸^l·乙氧基卜苯基）-2-乙氧基-丙酸之相同方法 製成。iH-NMR (400 MHz，CDC13) ·· 口1.16 (t，3H，J=6.7 Hz)， 1·52 (d，3H，J=6.8 Hz)，2.65-2.71 (dd，1H，J=6.9 Hz，13·7 Hz)， 2·74-2·80 (dd，1H，J=6.3 Hz，12.7 Hz)，2.96-2.99 (m，1H)， 3.04-3.08 (m，1H)，3.40-3.44 (m，2H)，3.56-3.64 (m，2H)，4.03 (br s，1H)，4.60 (q，ih，j=6.4 Hz)，6·48 (br s，1H)，6·76 (d， 2H，J=7.8 Hz)，6.85-6.88 (m，2H)，6.96-7.00 (m，4H)， 7.07-7.17 (m，3H)，7.30-7.35 (m，2H); MS (MH+) ·· 506.2。Example 80 2-ethoxy-3- {4- [l- (4-phenoxy-phenylethylaminemethylamidino) -ethoxy] -phenyl} _propionic acid (S, S) -3- (4 · {M2- (2-Chloro-phenyl) -ethylcarbamic acid ^ l · ethoxyphenylphenyl) -2-ethoxy-propionic acid production. iH-NMR (400 MHz, CDC13) ·· Port 1.16 (t, 3H, J = 6.7 Hz), 1.52 (d, 3H, J = 6.8 Hz), 2.65-2.71 (dd, 1H, J = 6.9 Hz , 13.7 Hz), 2.74-2 · 80 (dd, 1H, J = 6.3 Hz, 12.7 Hz), 2.96-2.99 (m, 1H), 3.04-3.08 (m, 1H), 3.40-3.44 ( m, 2H), 3.56-3.64 (m, 2H), 4.03 (br s, 1H), 4.60 (q, ih, j = 6.4 Hz), 6.48 (br s, 1H), 6.76 (d, 2H, J = 7.8 Hz), 6.85-6.88 (m, 2H), 6.96-7.00 (m, 4H), 7.07-7.17 (m, 3H), 7.30-7.35 (m, 2H); MS (MH +) ·· 506.2.

實例81 2-乙氧基-3-{4-[l-(3-三氟甲基_苯基乙基胺甲醯基）_乙氧基] -苯基卜丙酸 標題化合物係利用製備（S，S)-3-(4-{ 1-[2-(2-氯基-苯基）· 85504.doc -93- 200406371 乙基胺甲酸基]-乙乳基}-苯基）-2 -乙氧基-丙酸之相商 H万法 製成。W-NMR (400MHz，CDC13) : 口1.00 (br s，3H)，l 43 3H，J=6.8 Hz)，2.73-2.88 (m，3H)，2.96-3.00 (m，lfi) 3 · 21 - 3 · 2 6 (rn，1Ή)，3 · 4 6 - 3 · 5 2 (m，3 H)，3 · 8 8 (b r s，1H)，4 6 q 广 1H，J=6.4 Hz)，6.63-6.69 (m，3H)，7.10 (d，1H，J=7.8 Hz) 7 2〇 (d，1H，J=7.8 Hz)，7·29-7·36 (m，2H)，7.42 (d，1H，J=7.8 Hz)· MS (MH+) ·· 454.2。Example 81 2-ethoxy-3- {4- [l- (3-trifluoromethyl_phenylethylaminemethylamidino) _ethoxy] -phenylpropanoic acid The title compound was prepared using ( S, S) -3- (4- {1- [2- (2-Chloro-phenyl) 85504.doc -93- 200406371 Ethyl carbamate] -ethoxylactyl} -phenyl) -2 -Ethoxy-propionic acid phase quotient H Wanfa. W-NMR (400MHz, CDC13): 1.00 (br s, 3H), l 43 3H, J = 6.8 Hz), 2.73-2.88 (m, 3H), 2.96-3.00 (m, lfi) 3 · 21-3 · 2 6 (rn, 1Ή), 3 · 4 6-3 · 5 2 (m, 3 H), 3 · 8 8 (brs, 1H), 4 6 q wide 1H, J = 6.4 Hz), 6.63-6.69 (m, 3H), 7.10 (d, 1H, J = 7.8 Hz) 7 2〇 (d, 1H, J = 7.8 Hz), 7.29-7 · 36 (m, 2H), 7.42 (d, 1H, J = 7.8 Hz) MS (MH +) 454.2.

實例82 3-(4-{1-[2-(2,6-二氯基-苯基）-乙基胺甲醯基]-乙氧基}_苯基 -2-乙氧基-丙酸 標題化合物係利用製備（S，S)-3-(4-{l-[2-(2-氯基-苯基）-乙基胺甲醯基]•乙氧基}-苯基）-2-乙氧基-丙酸之相同方法 製成。(400 MHz，CDC13) : 口1.05 (t，3H，J=6.4 Hz)， 1·45 (d，3H，J=6.8 Hz)，2·80·2·86 (dd，1H，J=6.9 Hz, 13·7 Hz)， 2.97-3.01 (d，1H，J=13.2 Hz)，3.10-3.18 (m，2H)，3.22-3.30 (m，1H)，3·46-3·62 (m，3H)，3.92 (br s，1H)，4·56 (q，1H，J=6.4 Hz)，6.71-6.77 (m，3H)，7.05 (t，1H，J=7.8 Hz)，7.12 (d，2H， Hz)，7.22 (d，2H，J=7.8 Hz); MS (MH+) : 454.1。Example 82 3- (4- {1- [2- (2,6-dichloro-phenyl) -ethylaminomethylmethyl] -ethoxy} _phenyl-2-ethoxy-propionic acid The title compound was prepared using (S, S) -3- (4- {l- [2- (2-chloro-phenyl) -ethylaminomethylmethyl] • ethoxy} -phenyl) -2 -Ethoxy-propionic acid. (400 MHz, CDC13): 1.05 (t, 3H, J = 6.4 Hz), 1.45 (d, 3H, J = 6.8 Hz), 2.80 · 2 · 86 (dd, 1H, J = 6.9 Hz, 13.7 Hz), 2.97-3.01 (d, 1H, J = 13.2 Hz), 3.10-3.18 (m, 2H), 3.22-3.30 (m, 1H ), 3.46-3.62 (m, 3H), 3.92 (br s, 1H), 4.56 (q, 1H, J = 6.4 Hz), 6.71-6.77 (m, 3H), 7.05 (t, 1H, J = 7.8 Hz), 7.12 (d, 2H, Hz), 7.22 (d, 2H, J = 7.8 Hz); MS (MH +): 454.1.

85504.doc . 94 . 200406371 實例83 2-乙氧基-3-(ί·{ΐ-[2气‘乙基_苯基p乙基胺甲醯基乙氧美} -苯基）-丙酸 標題化合物係利用製備（8,3)-3-(4-{1-[2-(2-氯基_笨美） 乙基胺甲醯基]-乙氧基卜苯基）-2-乙氧基_丙酸之相同方、去 製成。iH-NMR (4〇〇 MHz，CDC13) : 口1.16 (t，3H，j=6 8 心） 1·21 (t，3Η，J=7.6 Ηζ)，1·49 (d，3Η，J=6.4 Ηζ)，2·6〇 (q，2η85504.doc. 94. 200406371 Example 83 2-ethoxy-3- (ί · {ΐ- [2-Gas'ethyl_phenylpethylaminemethylamidoethoxymei} -phenyl) -propionic acid The title compound was prepared using (8,3) -3- (4- {1- [2- (2-chloro-benzyl) ethylaminomethylmethyl] -ethoxyphenylphenyl) -2-ethyl The same formula of oxy-propionic acid is made. iH-NMR (400 MHz, CDC13): 1.16 (t, 3H, j = 6 8 hearts) 1.21 (t, 3Η, J = 7.6 Ηζ), 1.49 (d, 3Η, J = 6.4 Ηζ), 2.60 (q, 2η

J=6.8 Ηζ)，2·60-2·68 (m，1Η)，2·73-2·80 (m，1Η)，2·94_3 〇〇 (dd，1Η，J=Z3 Ηζ，14·2 Ηζ)，3.04-3.09 (dd，1Η，J=4.3 η7 〜 ιζ，ΐ4·2 Ηζ)，3·40-3·46 (m，2Η)，3.52-3.65 (m，2Η)，4.03 (dd , 、1Η， J=4.3 Ηζ，7.8 Ηζ)，4·62 (q，1Η，J=6.8 Ηζ)，6·52 (t，ιηJ = 6.8 Ηζ), 2.60-2 · 68 (m, 1Η), 2.73-2 · 80 (m, 1Η), 2.94_3 〇〇 (dd, 1Η, J = Z3 Ηζ, 14 · 2 Ηζ), 3.04-3.09 (dd, 1Η, J = 4.3 η7 to ιζ, ΐ4.2 Ηζ), 3.40-3 · 46 (m, 2Η), 3.52-3.65 (m, 2Η), 4.03 (dd, , 1Η, J = 4.3 Ηζ, 7.8 Ηζ), 4.62 (q, 1Η, J = 6.8 Ηζ), 6.52 (t, ιη

JU Ηζ)，6.76 (d，2Η，J=8.8 Ηζ)，6·95 (d，2Η，J=7.8 Hz)，7 〇6 (d 2Η，J=7.8 Ηζ)，7·18 (d，2Η，J=8.3 Hz); MS (ΜΗ+) ·· 414 2。’JU Ηζ), 6.76 (d, 2Η, J = 8.8 Ηζ), 6.95 (d, 2Η, J = 7.8 Hz), 7 〇6 (d 2Η, J = 7.8 Ηζ), 7.18 (d, 2Η , J = 8.3 Hz); MS (ΜΗ +) · 414 2. ’

實例84 氧基} 2-乙氧基-3-(4-{1-[2-(4-乙基·苯基）-乙基胺甲醯基]_乙 -苯基）-丙酸 標題化合物係利用製備（S，S)-3-(4-{l-[2-(2-氣基_笨義） ‘ 乙基胺甲δά基]-乙氧基}•苯基）-2-乙氧基-丙酸之相同方、去 、 製成。W-NMR (400 MHz，CDC13) : []〇·97 (t，3H，j=7 δ ，’·8 Hz)， 1·19 (t，3Η，J=7.6 Ηζ)，1.21 (t，3Η，J=6.8 Ηζ)，1·8(Μ 9〇 (仿: 85504.doc -95- 200406371 1H)，1.90-1.98 (m，1Η)，2·60 (q，2H，J=7.3 Hz)，2.60-2.68 (m， 1H)，2.72-2.19_(m，1H)，2.99 (dd，1H，J=7.3 Hz，14.2 Hz)，3.08 (dd，1H，J=3.9 Hz，12.7 Hz)，3.40-3.48 (m，2H)，3.52-3.64 (m， 2H)，4.02-4.07 (m，1H)，4.48 (dd，1H，J=4.8 Hz，6·8 Hz)，6.54 (t，1H，J=6.4 Hz)，6.60 (d，2H，J=8.8 Hz)，6.87 (d，2H，J=8.3 Hz)，6.96 (d，2H，J=7.8 Hz)，7.02 (d，2H，J=8.3 Hz); MS (MH+) ： 428.2 〇Example 84 Oxyoxy} 2-ethoxy-3- (4- {1- [2- (4-ethyl · phenyl) -ethylaminomethylmethyl] _ethyl-phenyl) -propionic acid It is prepared by using (S, S) -3- (4- {l- [2- (2-Gas group_stupid) 'ethylamine methylδάyl] -ethoxy} • phenyl) -2-ethyl The same formula of oxy-propionic acid, go, and make. W-NMR (400 MHz, CDC13): [] 〇 97 (t, 3H, j = 7 δ, '· 8 Hz), 1.19 (t, 3Η, J = 7.6 Ηζ), 1.21 (t, 3Η , J = 6.8 Ηζ), 1.8 (M 9〇 (simulation: 85504.doc -95- 200406371 1H), 1.90-1.98 (m, 1Η), 2.60 (q, 2H, J = 7.3 Hz), 2.60-2.68 (m, 1H), 2.72-2.19_ (m, 1H), 2.99 (dd, 1H, J = 7.3 Hz, 14.2 Hz), 3.08 (dd, 1H, J = 3.9 Hz, 12.7 Hz), 3.40 -3.48 (m, 2H), 3.52-3.64 (m, 2H), 4.02-4.07 (m, 1H), 4.48 (dd, 1H, J = 4.8 Hz, 6.8 Hz), 6.54 (t, 1H, J = 6.4 Hz), 6.60 (d, 2H, J = 8.8 Hz), 6.87 (d, 2H, J = 8.3 Hz), 6.96 (d, 2H, J = 7.8 Hz), 7.02 (d, 2H, J = 8.3 Hz); MS (MH +): 428.2

實例85 2 -乙乳基-3-(4-{l-[2-(4 -乙基-苯基）-乙基胺甲酸基]-丙氧基} -苯基）-丙酸 標題化合物係利用製備（8,8)-3-(4-{1-[2-(2-氯基-苯基）-乙基胺甲酸基]-乙氧基}-苯基）-2-乙氧基-丙酸之相同方法 製成。(400 MHz，CDC13) ·· 口0.80 (t，3H，J=6.8 Hz)， 1.03 (t，3H，J=7.6 Hz)，1.10-1.20 (m，11H)，2.85-2.89 (m，1H)， 2.91 (dd? 1H? J=7.3 Hz? 14.2 Hz)? 2.98 (dd5 1H? J=4.8 Hz5 14.2 Hz)，2.96-3.01 (m，1H)，3.37-3.43 (m，2H)，3.50-3.57 (m，2H)， 3.99 (dd，1H，J=4.4 Hz，7.3 Hz)，4.52 (t，1H，J=6.4 Hz)，6.54 (t，、lH，J=6.4 Hz)，6.68 (d，2H，J=8.3 Hz)，7.02 (d，2H，J=8.3 Hz); MS (MH+) : 380.2。 85504.doc -96- 200406371Example 85 2-Ethoxy-3- (4- {l- [2- (4-ethyl-phenyl) -ethylcarbamate] -propoxy} -phenyl) -propionic acid Preparation of (8,8) -3- (4- {1- [2- (2-chloro-phenyl) -ethylcarbamate] -ethoxy} -phenyl) -2-ethoxy -Made in the same way as propionic acid. (400 MHz, CDC13) ·· Port 0.80 (t, 3H, J = 6.8 Hz), 1.03 (t, 3H, J = 7.6 Hz), 1.10-1.20 (m, 11H), 2.85-2.89 (m, 1H) , 2.91 (dd? 1H? J = 7.3 Hz? 14.2 Hz)? 2.98 (dd5 1H? J = 4.8 Hz5 14.2 Hz), 2.96-3.01 (m, 1H), 3.37-3.43 (m, 2H), 3.50-3.57 (m, 2H), 3.99 (dd, 1H, J = 4.4 Hz, 7.3 Hz), 4.52 (t, 1H, J = 6.4 Hz), 6.54 (t, lH, J = 6.4 Hz), 6.68 (d, 2H, J = 8.3 Hz), 7.02 (d, 2H, J = 8.3 Hz); MS (MH +): 380.2. 85504.doc -96- 200406371

實例86 2-乙氧基-3-(4-{1^2-(4-苯氧基-苯基）-乙基胺甲醯基l·丙氧 基卜苯基）-丙酸 標題化合物係利用製備（85)-3-(4-{1-[2-(2-氯基-苯基）· 乙基胺甲乙氧基卜苯基）-2-乙氧基-丙酸之相同方法 製成。h-NMR (400 MHz，CDC13，一 種立體異構物）：[]〇·92 (t，3Η，J=7.3 Ηζ)，1·1〇 (t，3Η，J=6.8 Hz)，1.74-1.82 (m，1Η)， 1.86-1.891 (m，1Η)，2.56-2.62 (m，1Η)，2·64_2·71 (m，1Η)， 2.86 (dd，1H，J=7.3 Hz，14.2 Hz)，2.98 (dd，1H，J=4.4 Hz，14.2 Hz)，3.33-3.40 (m，2H)，3.49-3.57 (m，2H)，3·95-3·99 (m，1H)， 4.41 (dd，1H，J=4.4 Hz，6.8 Hz)，6.40 (t，1H，J=6.4 Hz)，6·70 (d，2H，J=8.3 Hz)，6.78 (d，2H，J=8.8 Hz)，6.88-6.94 (m，4H)， 7.01-7.06 (m，1H)，7.08 (d，2H，J=8.8 Hz)，7.25 (d，1H，J=7.4 85504.doc -97- 200406371Example 86 2-ethoxy-3- (4- {1 ^ 2- (4-phenoxy-phenyl) -ethylaminomethylmethyl-1-propoxyphenyl) -propionic acid Prepared by the same method as (85) -3- (4- {1- [2- (2-Chloro-phenyl) · ethylaminemethylethoxybuphenyl) -2-ethoxy-propionic acid to make. h-NMR (400 MHz, CDC13, a stereoisomer): [] 〇 92 (t, 3Η, J = 7.3 Ηζ), 1.10 (t, 3Η, J = 6.8 Hz), 1.74-1.82 (m, 1Η), 1.86-1.891 (m, 1Η), 2.56-2.62 (m, 1Η), 2.64_2 · 71 (m, 1Η), 2.86 (dd, 1H, J = 7.3 Hz, 14.2 Hz), 2.98 (dd, 1H, J = 4.4 Hz, 14.2 Hz), 3.33-3.40 (m, 2H), 3.49-3.57 (m, 2H), 3.95-3 · 99 (m, 1H), 4.41 (dd, 1H, J = 4.4 Hz, 6.8 Hz), 6.40 (t, 1H, J = 6.4 Hz), 6.70 (d, 2H, J = 8.3 Hz), 6.78 (d, 2H, J = 8.8 Hz), 6.88 -6.94 (m, 4H), 7.01-7.06 (m, 1H), 7.08 (d, 2H, J = 8.8 Hz), 7.25 (d, 1H, J = 7.4 85504.doc -97- 200406371

Hz)，7.27 (d，1H，J=7.8 Hz); MS (MH+) : 492.1。Hz), 7.27 (d, 1H, J = 7.8 Hz); MS (MH +): 492.1.

實例87 3-(4-{J幕己基-[2-(4 -乙基-苯基）-乙基胺甲驗基]-甲氧基}-苯 基）。2-乙氧基-丙酸Example 87 3- (4- {J curtain hexyl- [2- (4-ethyl-phenyl) -ethylaminemethanine] -methoxy} -phenyl). 2-ethoxy-propionic acid

標題化合，係利用製備（S，S)-3-(4-{l-[2-(2-氯基-苯基）-乙基胺甲醯:基]·乙氧基}-苯基）-2_乙氧基-丙酸之相同方法 製成。W-NMR (400 MHz，CDC13) : 口1.16 (t，3H，J=7.8 Hz)，The title compound was prepared using (S, S) -3- (4- {l- [2- (2-chloro-phenyl) -ethylamine formamidine: yl] · ethoxy} -phenyl) -2_ethoxy-propionic acid is prepared in the same way. W-NMR (400 MHz, CDC13): port 1.16 (t, 3H, J = 7.8 Hz),

1.20 (t，3H，J=7.6 Hz)，1.20-1.30 (m，6H)，1·49 (d，3H，J=6.8 Hz)，2.08 (s，2H)，2.60 (q，2H，J=7.3 Hz)，2.64-2.69 (m，1H)， 2.72-2.80 (m，1H)5 2·97 (dd，1H，J=6.4 Hz, 14·2 Hz)，3.08 (dd， 1H，J=4.4 Hz，14.2 Hz)，3.38-3.48 (m，2H)，3·52-3·66 (m，2H)， 3.80-3.90 (m，1H)，4.02 (dd，1H，J=4.4 Hz，7·8 Hz)，4·62 (q， 1H，J=6.9 Hz&quot;)，4.93-5.02 (m，1H)，6.53 (t，1H，J=5.9 Hz)，6.76 (d，2H，J=8.8 Hz)，6.95 (d，2H，J=8.3 Hz)，7.07 (d，2H，J=7.8 Hz)，7.17 (d，2H，J=8.3 Hz); MS (MH+) : 483.2。1.20 (t, 3H, J = 7.6 Hz), 1.20-1.30 (m, 6H), 1.49 (d, 3H, J = 6.8 Hz), 2.08 (s, 2H), 2.60 (q, 2H, J = 7.3 Hz), 2.64-2.69 (m, 1H), 2.72-2.80 (m, 1H) 5 2.97 (dd, 1H, J = 6.4 Hz, 14 · 2 Hz), 3.08 (dd, 1H, J = 4.4 Hz, 14.2 Hz), 3.38-3.48 (m, 2H), 3 · 52-3 · 66 (m, 2H), 3.80-3.90 (m, 1H), 4.02 (dd, 1H, J = 4.4 Hz, 7 · 8 Hz), 4.62 (q, 1H, J = 6.9 Hz &quot;), 4.93-5.02 (m, 1H), 6.53 (t, 1H, J = 5.9 Hz), 6.76 (d, 2H, J = 8.8 Hz ), 6.95 (d, 2H, J = 8.3 Hz), 7.07 (d, 2H, J = 7.8 Hz), 7.17 (d, 2H, J = 8.3 Hz); MS (MH +): 483.2.

85504.doc -98- 200406371 2_乙氧基-3-(4-{l-[2-(4 -乙基-苯基）-乙基胺甲酸基]-2_苯基- ^ 乙氧基}-苯基）-丙酸 標題化合物係利用製備（3,3)-3-(4-{1-[2-(2-氯基-苯基）-乙基胺甲醯基]-乙氧基}-苯基）-2-乙氧基-丙酸之相同方法 製成。h-NMR (400 MHz，CDC13) : []1.16 (t，3H，J=7.8 Hz)，1.21 (t，3H，J=7.3 Hz)，2.55-2.65 (m，4H)，2.96 (dd，1H，J=8.3 Hz，14.2 Hz)，3·04 (dd，1H，J=3.9 Hz，14.2 Hz)，3.12 (dd，1H，J=6.8 Hz, 14.2 Hz)，3·24 (dd，1H，J=3.4 Hz，14·2 Hz)，3.39-3.44 (m，3H)， 3·59-3·65 (nCIH)，4·02 (dd，1H，J=4.4 Hz，7.8 Hz)，4.62 (q，1H， J=3.4 Hz)，6.40 (t，2H，J=5.8 Hz)，6.69 (d，2H，J=8.8 Hz)，6.86 (d， 2H，J=7.8 Hz)，7.04 (d，2H，J=8.3 Hz)，7.13 (d，2H，J=8.8 Hz)， 7.20-7,30 (m，5H); MS (MH+) : 491.4。85504.doc -98- 200406371 2_ethoxy-3- (4- {l- [2- (4-ethyl-phenyl) -ethylcarbamate] -2-phenyl- ^ ethoxy } -Phenyl) -propionic acid The title compound was prepared using (3,3) -3- (4- {1- [2- (2-chloro-phenyl) -ethylaminomethylmethyl] -ethoxy Group} -phenyl) -2-ethoxy-propionic acid. h-NMR (400 MHz, CDC13): [] 1.16 (t, 3H, J = 7.8 Hz), 1.21 (t, 3H, J = 7.3 Hz), 2.55-2.65 (m, 4H), 2.96 (dd, 1H , J = 8.3 Hz, 14.2 Hz), 3.04 (dd, 1H, J = 3.9 Hz, 14.2 Hz), 3.12 (dd, 1H, J = 6.8 Hz, 14.2 Hz), 3.24 (dd, 1H, J = 3.4 Hz, 14.2 Hz), 3.39-3.44 (m, 3H), 3.59-3 · 65 (nCIH), 4.02 (dd, 1H, J = 4.4 Hz, 7.8 Hz), 4.62 ( q, 1H, J = 3.4 Hz), 6.40 (t, 2H, J = 5.8 Hz), 6.69 (d, 2H, J = 8.8 Hz), 6.86 (d, 2H, J = 7.8 Hz), 7.04 (d, 2H, J = 8.3 Hz), 7.13 (d, 2H, J = 8.8 Hz), 7.20-7, 30 (m, 5H); MS (MH +): 491.4.

堂例89 : 2•漠-Ν-『2·(4-苯氫某-笨基乙基1-乙醯胺 將4-苯氧苯乙胺（213.28 amu、2.5克、1當量、10.8毫莫 耳、1.09克/毫升、2·3毫升）加入三頸燒瓶。隨同50毫升CH2C12 ’添加溴化溴乙酸（201·86 amu、1.1當量、11.8毫莫耳、2.4 克、2.317克/毫升、1·〇3毫升）、吡啶（no amu、5當量、4.27 克、0.978克/毫升、54毫莫耳、4.4毫升）。令反應於室溫攪 拌2小時。去除CH2C12，並溶混合物於2〇〇毫升EtOAc。以鹽 液與水（各200毫升）洗有機層。分開有機層，經硫酸鈉脫水 並旋轉蒸餾以生成1.56克材料。MS [EI+] 334 (M+H)+，MS [EI-]332 (M-H)+。 85504.doc -99- 200406371Example 89: 2 • Mo-N- 『2 · (4-phenylhydrogen-benzylethyl 1-acetamidine 4-phenoxyphenethylamine (213.28 amu, 2.5 g, 1 equivalent, 10.8 mmol Ear, 1.09 g / ml, 2.3 ml) into a three-necked flask. Accompany with 50 ml of CH2C12 'bromoacetic acid (201.86 amu, 1.1 equivalents, 11.8 mmol, 2.4 g, 2.317 g / ml, · 03 ml), pyridine (no amu, 5 equivalents, 4.27 g, 0.978 g / ml, 54 mmol, 4.4 ml). The reaction was allowed to stir at room temperature for 2 hours. The CH2C12 was removed and the mixture was dissolved in 2000. Ml of EtOAc. Wash the organic layer with saline and water (200 ml each). Separate the organic layer, dehydrate over sodium sulfate and spin distillation to produce 1.56 g of material. MS [EI +] 334 (M + H) +, MS [EI- ] 332 (MH) +. 85504.doc -99- 200406371

對掌體 實例90 : 2-甲基-2·笨氣基-3-(4-ί「2-(4-苯氣某-笨基）-乙基胺 甲醯基1-甲氣基卜笨基丙酸Example of palm body 90: 2-methyl-2 · benzyl-3- (4-, "2- (4-benzyl-benzyl) -ethylaminomethylmethyl-l-methylbenzyl Propionic acid

將3 - (4 -經基-苯基）-2-甲基-2-苯氧基-丙酸乙g旨（300.352 amu、1當量、225毫克、0.76毫莫耳）加入三頸燒瓶。隨同氫 化鈉（24 amu、1.1當量、0.82毫莫耳、20毫克、33毫克之懸 浮於礦物油的60%溶液），添加20毫升無水二吟垸。令反應於 室溫攪拌15分鐘。添加2-溴基-N-[2-(4-苯氧基-苯基）-乙基]-乙醯胺（333.1 amu、250毫克、1當量、0.76毫莫耳），並令反 應於100°C ^拌6小時。將反應混合物加至200毫升EtOAc。以 鹽液與水（各兩次，200毫升）洗。令有機層經硫酸鈉脫水並 濃縮以生成250毫克粗產物。令材料經chromatatron分開（含 10-70% EtOAc/己烷）。分離出產物污潰並濃縮，以生成25 毫克所需之乙酯。溶材料於5毫升EtOH。隨同5毫升之5當量 濃度NaOH加至旋轉輸送管。於50°C、氮氣壓下隔夜攪拌。 將反應混合物加至100毫升EtOAc。經10毫升濃HC1酸化。添 加100毫升鹽液，並去除有機層。濃縮以生成20毫升產物。 85504.doc -100- 200406371 MS [EI+] 526 (M+H) +，MS [EI-] 524 (M-H)+。3 g- (4-Cylenyl-phenyl) -2-methyl-2-phenoxy-propionic acid (300.352 amu, 1 equivalent, 225 mg, 0.76 mmol) was added to a three-necked flask. Accompanying sodium hydride (24 amu, 1.1 equivalents, 0.82 millimoles, 20 mg, 33 mg suspended in a 60% solution in mineral oil), 20 ml of anhydrous diyin was added. The reaction was allowed to stir at room temperature for 15 minutes. Add 2-bromo-N- [2- (4-phenoxy-phenyl) -ethyl] -acetamidamine (333.1 amu, 250 mg, 1 equivalent, 0.76 mmol) and let the reaction react at 100 ° C ^ Stir for 6 hours. The reaction mixture was added to 200 mL of EtOAc. Wash with saline and water (twice, 200 ml each). The organic layer was dehydrated over sodium sulfate and concentrated to give 250 mg of a crude product. The material was separated by chromatatron (containing 10-70% EtOAc / hexane). The product was isolated and fouled and concentrated to give 25 mg of the desired ethyl ester. Dissolve the material in 5 ml of EtOH. With 5 ml of 5 equivalents NaOH was added to the rotary tube. Stir overnight at 50 ° C under nitrogen pressure. The reaction mixture was added to 100 mL of EtOAc. Acidified with 10 ml of concentrated HC1. Add 100 ml of saline and remove the organic layer. Concentrated to yield 20 ml of product. 85504.doc -100- 200406371 MS [EI +] 526 (M + H) +, MS [EI-] 524 (M-H) +.

督例91 : 2-苯氧基-2-(4-{「2-(4-笨氣基-笨基乙基胺甲醯某μ〒氧苺} : -芊基V丁酸Example 91: 2-phenoxy-2- (4-{"2- (4-benzyl-benzylethylamine formamidine),: -Methyl V-butyric acid

標題化合物係利用製備2-甲基-2-苯氧基_3-(4-{[2-(4-苯 氧基-苯基)+乙基胺甲醯基]_甲氧基卜苯基）_丙酸之相同方 法’由2-(4-幾基_苄基）_2_苯氧基·丁酸乙酯製成。MS [EI+] 540 (M+H)+，MS [EI-] 538 (M-H)+。 85504.doc 實例92Oo^&gt;-Nr- ΟThe title compound was prepared by using 2-methyl-2-phenoxy_3- (4-{[2- (4-phenoxy-phenyl) + ethylaminomethylmethyl] _methoxyphenyl ) _The same method of propionic acid 'is made from 2- (4-quinyl_benzyl) _2_phenoxy · butyric acid ethyl ester. MS [EI +] 540 (M + H) +, MS [EI-] 538 (M-H) +. 85504.doc Example 92Oo ^ &gt; -Nr- Ο

-101 - 200406371 2-甲一基-3-(4.-{f2-(4-笨氣基-苽基乙某胺甲醯基μ甲_|^^ 基基）-2-(4-三氟甲氣某-茉氣某ν丙酸 標題化合物係利用製備2-甲基-2-苯氧基-3-(4-{[2-(4_苯 ~ 氧基-私基）-乙基胺甲酸基]-甲氧基卜苯基）_丙酸之相同方法-，由3-(4-羥基-芊基）-2-甲基-2-(4-三氟甲氧基-苯氧基）_丙酸 乙酯製成。MS [EI+] 610 (M+H)+，MS [El·] 608 (M-H)+。-101-200406371 2-methylmonoyl-3- (4 .- {f2- (4-benzyl-fluorenylethyl some amine methylamidino μmethyl_ | ^^ yl) -2- (4-tri The title compound of fluoromethyl-methane and molybdenum propionate was prepared by using 2-methyl-2-phenoxy-3- (4-{[2- (4_benzene ~ oxy-private) -ethyl Carbaminyl] -methoxyphenyl) _propionic acid-the same method, from 3- (4-hydroxy-fluorenyl) -2-methyl-2- (4-trifluoromethoxy-phenoxy Based on ethyl propionate. MS [EI +] 610 (M + H) +, MS [El ·] 608 (MH) +.

F 實例93 對掌體F Example 93 Pair of palms

NN

茉氫某·苽某乙基 - 甲氣某}•苽某）_雨鹼 : 祛過化口物係利用製備2-甲基-2-苯氧基-3-(4-{[2-(4-苯 氧基-苯基）、 夂胺甲醯基]-甲氧基卜苯基）_丙酸之相同方 法，由2-(4-翁其# #分 - 土本氧基）-3-(4_#呈基-苯基）·2-甲基-丙酸乙酉旨 - 85504.doc -102- 200406371 製成。MS [EI+] 544 (M+H)+，MS [EI-] 542 (M-Η)十。 一 實例94 (2S)-2-甲氧基-3-(4-{2-氧基-2-[4_(4-三氟甲基·苯基）-喊畊 -1-基]-乙氧基卜苯基）_丙酸 f。對掌體Molybdenum · Ethylethyl-methylazine} • Nine} _Racine: Preparation of 2-methyl-2-phenoxy-3- (4-{[2- ( 4-phenoxy-phenyl), amidomethyl] -methoxybuphenyl) _propanoic acid, the same method as 2- (4- 翁 其 # # 分-土 本 XY) -3 -(4- # Amino-phenyl) · 2-methyl-propionate ethyl acetate-85504.doc -102- 200406371. MS [EI +] 544 (M + H) +, MS [EI-] 542 (M-Η). An example of 94 (2S) -2-methoxy-3- (4- {2-oxy-2- [4_ (4-trifluoromethyl · phenyl) -dimethyl-1-1-yl] -ethoxy Gib phenyl) -propionic acid f. Palm body

步·驟1 : (2SJ^3-(4-第三-丁氧羰甲氧基-苯基）-2-甲氧基-丙酸 乙酯…Step · Step 1: (2SJ ^ 3- (4-Third-butoxycarbonylmethoxy-phenyl) -2-methoxy-propionic acid ethyl ester ...

令化合物（2S)-3-(4-羥基-苯基）-2-甲氧基-丙酸酯（實例1 、步驟1)(1.2克、5·3毫莫耳）溶於25毫升無水THF，並分次 加入NaH (3立0毫克、15.8毫莫耳）。約5分鐘後，於室溫下逐 滴添加溴乙酸第三-丁酯。令混合物於室溫攪拌2小時。溶 粗產物於乙酸乙酯（100毫升），並添加5% HC1溶液。令該混 合物經乙酸乙酯萃取（3X 100毫升），並令合併之有機層脫水 (MgS04)，然後真空濃縮。令粗產物經管柱層析（矽膠、已 烷/乙酸乙酯8·5 ·· 1.5)純化，以提供黃色油。 步騾2 : 2(S)-3-(4-羧甲氧基-苯基）_2_甲氧基-丙酸乙酯The compound (2S) -3- (4-hydroxy-phenyl) -2-methoxy-propionate (Example 1, Step 1) (1.2 g, 5.3 mmol) was dissolved in 25 ml of anhydrous THF And add NaH (3 mg 0 mg, 15.8 mmol) in portions. After about 5 minutes, tert-butyl bromoacetate was added dropwise at room temperature. The mixture was allowed to stir at room temperature for 2 hours. The crude product was dissolved in ethyl acetate (100 ml) and a 5% HC1 solution was added. The mixture was extracted with ethyl acetate (3 × 100 ml), and the combined organic layers were dehydrated (MgS04) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, hexane / ethyl acetate 8 · 5 ·· 1.5) to provide a yellow oil. Step 2: 2 (S) -3- (4-carboxymethoxy-phenyl) _2_methoxy-propionic acid ethyl ester

85504.doc •103- 令化合物（2S)-3-(4-第三-丁氧羰甲氧基_苯基）_2•甲氧基-丙酸乙酯（製4希物3、步驟1)(1.2克、3.5毫莫耳）溶於二氯甲 烷（5笔升），並添加三氟乙酸（5毫升）。令該混合物搅拌i小 時’並濃縮粗產物以提供黃色油。(CDC13，200.15 MHz) : 7.16 (d，2H，J=8.3)，6.75 (d，2H，J=8.3)，4.89 (s，2H)， 4.14 (c，2H，J=6.9)，3·94 (t，1H，J=6.9)，3·57 (dc，1H)，3.35 (dc，1H)，2.92 (d，2H，J=6.9)，1.23-1.10 (2t，6H)。 步驟3 · (2S)-2-甲氧基-3-(4_{2_氧基-2-[4-(4·三氟甲基-苯基) -喊畊-1_基]二乙氧基}苯基）·丙酸 對掌體85504.doc • 103- Make compound (2S) -3- (4-third-butoxycarbonylmethoxy_phenyl) _2 • methoxy-propionic acid ethyl ester (preparation 4 Greek 3, step 1) (1.2 g, 3.5 mmol) was dissolved in dichloromethane (5 strokes), and trifluoroacetic acid (5 ml) was added. The mixture was allowed to stir for i hours' and the crude product was concentrated to provide a yellow oil. (CDC13, 200.15 MHz): 7.16 (d, 2H, J = 8.3), 6.75 (d, 2H, J = 8.3), 4.89 (s, 2H), 4.14 (c, 2H, J = 6.9), 3.94 (t, 1H, J = 6.9), 3.57 (dc, 1H), 3.35 (dc, 1H), 2.92 (d, 2H, J = 6.9), 1.23-1.10 (2t, 6H). Step 3 (2S) -2-methoxy-3- (4_ {2_oxy-2- [4- (4 · trifluoromethyl-phenyl) -dimethyl-1-1-yl] diethoxy Group} phenyl) · propionic acid

標題化合物係經由用以製備（2S，1R)-2-乙氧基_3-(4_{1_ [2-(4-苯氧基-苯基）_乙基胺甲醯基]_乙氧基卜苯基）_丙酸（實 例1、步驟3)之相同方法由（2S)_3气4_羧甲氧基-苯基甲氧 基-丙酸乙酯化（製備物3、步驟2)與1-(4-三氟甲基-苯基）_哌 ’製備’以生產無色油。C23H25F3N05 [M+H]+之MS (ES): 467。 實例95 (2S)-3-(4-{[(二苯基_4_基甲基）_胺甲醯基]_甲氧基卜苯基） _2_甲氧基-丙酸The title compound is used to prepare (2S, 1R) -2-ethoxy_3- (4_ {1_ [2- (4-phenoxy-phenyl) _ethylaminomethyl}] _ ethoxy (Phenyl) _propionic acid (Example 1, step 3) The same method was (2S) _3 gas 4_carboxymethoxy-phenylmethoxy-propionic acid ethyl ester (preparation 3, step 2) 1- (4-trifluoromethyl-phenyl) -piperone is 'prepared' to produce a colorless oil. C23H25F3N05 [M + H] + for MS (ES): 467. Example 95 (2S) -3- (4-{[(diphenyl_4-ylmethyl) _aminomethylmethyl] _methoxyphenylphenyl) _2_methoxy-propionic acid

85504.doc -104- 200406371 標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4-{l-[2-(4-苯氧基^苯基）_乙基胺甲醯基]-乙氧基）苯基）_丙酸（實 例1、步騾3)之相同方法由（2S)-3-(4-羧甲氧基-苯基）-2-甲氧 基-丙酸乙酯（製備物3、步驟2)與^二苯基_4_基-甲胺製備， 以生產無色油。C25h25N05 [M+H]+之 MS (ES) : 420。 實例96 (2S)_2-甲氧基-M4-[(甲基-莕-1-基甲基-胺甲醯基）-甲氧基] 苯基}-丙酸85504.doc -104- 200406371 The title compound was used to prepare (2S, lR) -2-ethoxy-3- (4- {l- [2- (4-phenoxy ^ phenyl) _ethyl Aminomethylamino] -ethoxy) phenyl) _propionic acid (Example 1, step 3) The same method as (2S) -3- (4-carboxymethoxy-phenyl) -2-methoxy Ethyl-propionate (Preparation 3, Step 2) and diphenyl-4-yl-methylamine were prepared to produce a colorless oil. C25h25N05 [M + H] + MS (ES): 420. Example 96 (2S) _2-methoxy-M4-[(methyl-fluoren-1-ylmethyl-aminomethylamidino) -methoxy] phenyl} -propionic acid

對掌體 標題化合物係經由用以製備（2S，lR)-2·乙氧基-3-(4-0-[2-(4-苯氧基-苯基&gt;乙基胺甲醯基卜乙氧基丨苯基）_丙酸（實 例1、步驟3)之相同方法由（2S)-3-(4-羧甲氧基-苯基）-2-甲氧 基-丙酸乙醋（製備物3、步驟2)與甲基_莕-1-基甲胺製備，以 生產無色油 7 C24H25n〇5 [M+H]+之 MS (ES) : 408。 實例97 (2S)_3-{4-[2_(4_二苯甲基-哌畊基）_2_氧基-乙氧基]_苯基} -2 -甲乳基-丙The title compound of palmar is used to prepare (2S, 1R) -2 · ethoxy-3- (4-0- [2- (4-phenoxy-phenyl)> ethylaminomethylmethyl The same method of ethoxy 丨 phenyl) _propionic acid (Example 1, step 3) is (2S) -3- (4-carboxymethoxy-phenyl) -2-methoxy-propionic acid ethyl acetate ( Preparation 3, step 2) and methyl-fluoren-1-ylmethylamine were prepared to produce colorless oil 7 C24H25n05 [M + H] + MS (ES): 408. Example 97 (2S) _3- { 4- [2_ (4_benzyl-piperidinyl) _2_oxy-ethoxy] _phenyl} -2 -methyllactyl-propyl

85504.doc -105- 200406371 標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4-{l_ [2-(4-苯氧基·笨基）-乙基胺甲醯基]-乙氧基}苯基）-丙酸（實 例1、步驟3)之相同方法由（2S)-3-(4-羧甲氧基-苯基）-2-甲氧 基-丙酸乙醋（製備物3、步驟2)與1-二苯甲基-哌畊製備，以 生產無色油。C29H32N205 [M+H]+之 MS (ES) : 489。 實例98 [雙_(4_氟基-苯基）-甲基]-哌畊小基卜2-氧 基-乙氧基)·苯基]-2-甲氧基-丙酸 : 對掌體85504.doc -105- 200406371 The title compound is used to prepare (2S, lR) -2-ethoxy-3- (4- {l_ [2- (4-phenoxy · benzyl) -ethylamine Methenyl] -ethoxy} phenyl) -propionic acid (Example 1, step 3) The same method is used for (2S) -3- (4-carboxymethoxy-phenyl) -2-methoxy- Ethyl propionate (Preparation 3, Step 2) was prepared with 1-benzyl-piperon to produce a colorless oil. C29H32N205 [M + H] + MS (ES): 489. Example 98 [Bis (4-fluoro-phenyl) -methyl] -piperonyl 2-oxo-ethoxy) · phenyl] -2-methoxy-propionic acid: palmar body

標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4-{1-[2-(4-苯氧基-苯基&gt; 乙基胺甲醯基]_乙氧基丨苯基）_丙酸（實 例1、步驟3立^相同方法由（2S)-3-(4-羧甲氧基-苯基）_2-甲氧 基-丙酸乙酯（製備物3、步騾2)與1-[雙-(4-氟-苯基）-甲基]-哌畊製備’以生產無色油。C29H3gF2N2〇5 [M+H]+之MS (ES) :525。 實例99 (2S)-2-甲氧基-3-(4-{[2-(4-苯氧基-苯基）_乙基胺甲醯基]_甲 氧基}-苯基）_丙酸 85504.doc -106- 200406371The title compound is used to prepare (2S, 1R) -2-ethoxy-3- (4- {1- [2- (4-phenoxy-phenyl)> ethylaminomethyl} -ethyl Oxy 丨 phenyl) _propionic acid (Example 1, Step 3) ^ same method from (2S) -3- (4-carboxymethoxy-phenyl) _2-methoxy-propionic acid ethyl ester (preparation 3. Step 2) Prepared with 1- [bis- (4-fluoro-phenyl) -methyl] -pigon 'to produce colorless oil. MS (ES) of C29H3gF2N205 (M + H) +: 525 Example 99 (2S) -2-methoxy-3- (4-{[2- (4-phenoxy-phenyl) _ethylaminemethylmethyl] _methoxy} -phenyl) _ Propionate 85504.doc -106- 200406371

標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4-{l-[1(4·苯氧基-笨基）_乙基胺甲醯基]_乙氧基}苯基丙酸（實 例1、步騾3)之相同方法、由（28)_3-(4_幾甲氧基_苯基）甲氧 基-丙酸乙酉^製備物3、步驟2)與2-(4-苯氧基-苯基乙胺製 備，以生產無色油。C26H27N06 [M+H]+之 MS (ES) : 450。 實例100 對掌體 (2δ)_3_{4_[2·(3,4·二氫-1H-異喳啉-2-基）-2-氧基-乙氧基]_苯 基}-2-甲氧基-丙酸The title compound is used to prepare (2S, lR) -2-ethoxy-3- (4- {l- [1 (4 · phenoxy-benzyl) _ethylaminomethylmethyl] _ethoxy Group} phenylpropionic acid (Example 1, step 3), the same method as described in (28) _3- (4_Equimethoxy_phenyl) methoxy-propionic acid ethyl ^ Preparation 3, step 2) Prepared with 2- (4-phenoxy-phenylethylamine) to produce a colorless oil. MS (ES) of C26H27N06 [M + H] +: 450. Example 100 Palm body (2δ) _3_ {4_ [2 · (3,4 · Dihydro-1H-isofluorin-2-yl) -2-oxy-ethoxy] -phenyl} -2-methoxy-propionic acid

標題化合、係經由用以製備（2S，1R)_2_乙氧基 [2-(4-苯氧基-苯基）_乙基胺甲醯基]-乙氧基丨苯基丙酸（實 例1、步驟3)之相同方法由（2S)-3-(4-叛甲氧基-苯基）-2-甲氧 基-丙酸乙酯（製備物3、步驟2)與1，2,3,4-四氫_異喳啉製備， 以生產育色油。C21H23N〇5 [M+H]+之MS (ES) : 370。 實例101 US)-3-{4-[(苄基_苯乙基_胺甲醯基）_甲氧基]_苯基卜2_甲氧 基-丙酸 85504.doc -107- 200406371The title compound is used to prepare (2S, 1R) _2_ethoxy [2- (4-phenoxy-phenyl) _ethylaminomethylmethyl] -ethoxy 丨 phenylpropionic acid (Example 1. The same method as in step 3) consists of (2S) -3- (4-retmethoxy-phenyl) -2-methoxy-propionic acid ethyl ester (Preparation 3, Step 2) and 1,2, Preparation of 3,4-tetrahydro-isoxoline to produce color oil. MS for C21H23NO5 [M + H] + (ES): 370. Example 101 US) -3- {4-[(benzyl_phenethyl_aminomethylamidino) _methoxy] _phenylbenzene 2-methoxy-propionic acid 85504.doc -107- 200406371

‘〜化口物係經由用以製備（23，11〇-2-乙氧基-3-(4-{1-[2-(4&quot;&quot;冬氧基-笨基）_乙基胺甲醯基]-乙氧基}苯基）-丙酸（實 例1步驟3)之相同方法由（2S)-3-(4-羧甲氧基-苯基）-2-甲氧 基-丙酸乙酯（製備物3、步騾2)與苄基_苯乙基_胺製備，以 生產 κ 色油、。C27H29N〇5 [M+H]+之 MS (ES) : 448。 實例102 (2S&gt;3_(‘{2_[4_(4·氟基-苯基）-哌畊_1_基]-2-氧基·乙氧基}- 苯基）-2-甲氧基-丙酸'~ Huakou system is used to prepare (23,11〇-2-ethoxy-3- (4- {1- [2- (4 &quot; &quot; dongoxy-benzyl) _ethylamine methyl Fluorenyl] -ethoxy} phenyl) -propionic acid (Example 3, step 3) from (2S) -3- (4-carboxymethoxy-phenyl) -2-methoxy-propionic acid Ethyl ester (Preparation 3, Step 2) and benzyl_phenethyl_amine were prepared to produce κ-color oil, MS (ES) of C27H29N05 [M + H] +: 448. Example 102 (2S &gt; 3 _ ('{2_ [4_ (4-Fluoro-phenyl) -pipen_1-yl] -2-oxy · ethoxy} -phenyl) -2-methoxy-propionic acid

對掌體 標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4-{1-[2-(4-苯氧基·苯基）_乙基胺甲醯基乙氧基丨苯基）_丙酸（實 例1、步驟3)之相同方法由（28&gt;3-(4_羧甲氧基_苯基）甲氧 基-丙酸乙酿（製備物3、步驟2)與1_(‘氟基_苯基）_哌畊製備 ，以生產無色油。C22H25FN205 [M+H]+之 MS (ES) : 417。 實例103 (2S)-2-甲氧基_3-4-{[2·(2·甲氧基-莕基）-乙基胺甲醯基]-甲 氧基卜苯基-丙酸 85504.doc -108- 200406371The title compound of palmar is used to prepare (2S, 1R) -2-ethoxy-3- (4- {1- [2- (4-phenoxy · phenyl) _ethylaminomethylmethyl) The same method of ethoxy 丨 phenyl) _propionic acid (Example 1, step 3) was prepared from (28 &gt; 3- (4_carboxymethoxy_phenyl) methoxy-propionic acid ethyl acetate (Preparation 3, Step 2) Preparation with 1 _ ('fluoro group_phenyl) _piperin to produce colorless oil. MS (ES) of C22H25FN205 [M + H] +: 417. Example 103 (2S) -2-methoxy_ 3-4-{[2 · (2 · methoxy-fluorenyl) -ethylaminomethylmethyl] -methoxyphenylphenyl-propionic acid 85504.doc -108- 200406371

匕口物係經由用以製備（2s，ir)_2_乙氧基_3_(4_{κ [2_(4_冬乳基-笨基）_乙基胺甲醯基]-乙氧基}苯基）_丙酸（實 ^ v驟3)之相同方法由（2S)_3_(4_叛甲氧基_苯基）冬甲氧 基-丙酸乙醋（製備物3、&gt;驟2)與卜(4_氯基_苯基）_2_甲基_哌〜 呼製備’以:生產黃色油。C23H27C1N205 [Μ+ΗΓ之MS (ES) ··】_ 447 。 、 ' 實例104 (2S)-3-(4-{2-[4-(3-氯基-苯基）喊啡小基]|氧基_乙氧基卜 冬基）_2_甲氧基-丙酸The dagger is used to prepare (2s, ir) _2_ethoxy_3_ (4_ {κ [2_ (4_winter milk-benzyl) _ethylamine formamyl] -ethoxy} benzene Group) _propionic acid (actually v 3) from (2S) _3_ (4_retmethoxy_phenyl) winter methoxy-ethyl propionate (preparation 3, &gt; step 2) With Bu (4-chloro_phenyl) _2_methyl_piper ~ Preparation: To produce yellow oil. C23H27C1N205 [MS (ES) of Μ + ΗΓ ··] _ 447. , 'Example 104 (2S) -3- (4- {2- [4- (3-Chloro-phenyl) oxorphine small group] | oxy_ethoxybutyrol) _2_methoxy-propionic acid

標題化合物係經由用以製備（2S，1Κ&gt;2_乙氧基_3_(4_{1_ - [2-(4-苯氧基-苯基）_乙基胺甲醯基卜乙氧基}苯基）_丙酸（實 例1、步驟3)之相同方法由（2S)-3气4_羧甲氧基_苯基）_2_甲氧 基-丙酸乙酯（製備物3、步騾2)與1-(3-氯基-苯基）_哌畊製備 a· ，以生產黃色油。C22H25C1N205 [M+H]+之MS (ES) : 433。 實例105 (2S)-3-(4-{2-[4-(4-氯基-芊基）-哌畊_ΐ·基]_2_氧基-乙氧基卜 - 85504.doc -109- 200406371 苯基）-2-甲氧基-丙酸 對掌體The title compound is used to prepare (2S, 1K &gt; 2_ethoxy_3_ (4_ {1_-[2- (4-phenoxy-phenyl) _ethylamine formamidine ethoxy} benzene Group) _propionic acid (Example 1, step 3) The same method as (2S) -3 gas 4_carboxymethoxy_phenyl) _2_methoxy-propionic acid ethyl ester (preparation 3, step 2) ) And 1- (3-chloro-phenyl) -piperin to prepare a · to produce a yellow oil. MS (ES) for C22H25C1N205 [M + H] +: 433. Example 105 (2S) -3- (4- {2- [4- (4-Chloro-fluorenyl) -piperazine_fluorenyl] _2_oxy-ethoxyb-85504.doc -109- 200406371 Phenyl) -2-methoxy-propionic acid

CICI

〇〇

秫遞化合物係經由用以製備（2S，1Κ)·2_乙氧基 [2-(4-苯氧基-苯基 &gt; 乙基胺甲醯基]-乙氧基）苯基丙酸（實 例1、步騾3)之相同方法由（2s)-3_(4_羧甲氧基_苯基兴甲氧 基-丙酸乙酿3：製備物3、步驟”與丨·^-氯基-苄基哌畊製備 ，以生產供色油。C23H27C1N205 [M+H]+之 MS (ES) : 447。 實例106 (2S)-3-(4-{2-[4-(2-氟基-苯甲基）_哌畊·;μ基卜2-氧基-乙氧基} -苯基）_2_甲氧基-丙酸The halogenated compound is used to prepare (2S, 1K) · 2-ethoxy [2- (4-phenoxy-phenyl &gt; ethylaminomethylmethyl] -ethoxy) phenylpropionic acid ( Example 1, Step 3) The same method was prepared from (2s) -3_ (4_carboxymethoxy_phenylhexylmethoxy-propionic acid ethyl alcohol 3: Preparation 3, step "and ^ -chloro group -Prepared by benzyl piperidine to produce a coloring oil. MS (ES) of C23H27C1N205 [M + H] +: 447. Example 106 (2S) -3- (4- {2- [4- (2-fluoro group) -Benzyl) _pigeng; μ keto 2-oxy-ethoxy} -phenyl) _2_methoxy-propionic acid

對掌體 標題化合物係經由用以製備（2S，1R)-2•乙氧基_3_(4_U_ [2-(4-苯氧基-苯基乙基胺甲醯基卜乙氧基}苯基丙酸（實 例1、步驟3)之相同方法由（2s)_3-(4-羧曱氧基―苯基）-2_甲氧 基-丙酸乙酯（製備物3、步驟2)與i-(2-氟基·苯基）-哌畊製備 ’以生產黃色油。C22H25FN2〇5 [m+H] +之 MS (ES) ·· 417。The title compound of palmar is used to prepare (2S, 1R) -2 • ethoxy_3_ (4_U_ [2- (4-phenoxy-phenylethylaminemethylamidinobuethoxy) phenyl The same method for propionic acid (Example 1, step 3) consists of (2s) _3- (4-carboxymethyloxy-phenyl) -2-methoxy-propionic acid ethyl ester (Preparation 3, Step 2) and i -(2-Fluoro.phenyl) -piperon 'to produce a yellow oil. MS (ES) of C22H25FN205 [m + H] + · 417.

實例106 A (2S)-3-(4-{[(苯并[1，3]-二氧戊環-5-基甲基）_胺甲醯基]•甲 85504.doc -110- 200406371 氧基卜苯基）-2-甲氧基-丙酸 〇 對掌體Example 106 A (2S) -3- (4-{[(Benzo [1,3] -dioxolane-5-ylmethyl) _aminomethylfluorenyl] • methyl 85504.doc -110- 200406371 oxygen Phenylphenyl) -2-methoxy-propionic acid

裇越化合物係經由用以製備（2S，1R)_2_乙氧基 [2-(4-苯氧基·苯基）_乙基胺甲醯基]_乙氧基丨苯基丙酸（實 例1、步騾3)之相同方法由（2s)-3彳‘羧甲氧基_苯基）_2_甲氧 基-丙酸乙酯（製備物3 v步驟”與。苯并二氧戊環_5_ 基-甲胺製舞一’以生產無色油。C2〇H21N07 [M+H]+之MS (ES) ：388 〇 ^ 實例106Β (2S)-3-(4-{[2_(4-溴基··苯基）_乙基胺甲醯基甲氧基卜苯基） -2-甲氧基-丙酸 〇Thermaltake compounds are used to prepare (2S, 1R) _2_ethoxy [2- (4-phenoxy · phenyl) _ethylaminomethylmethyl] _ethoxy 丨 phenylpropionic acid (Example 1. The same method as in step 骡 3) consists of (2s) -3 彳 'carboxymethoxy_phenyl) -2-methoxy-propionic acid ethyl ester (preparation 3 v step) and benzodioxolane _5_ based on methyl-methylamine to produce colorless oil. C2OH21N07 [M + H] + MS (ES): 388 〇 ^ Example 106B (2S) -3- (4-{[2_ (4- Bromo ·· phenyl) _ethylaminomethylmethylmethoxyphenyl) -2-methoxy-propionic acid

標題化合物係經由用以製備（2S，lR)-2·乙氧基-3-(4·{1_ [2-(4_苯氧基-苯基）_乙基胺甲醯基乙氧基}苯基）_丙酸（實 例1、步驟3)之相同方法由（2S)-3-(4-羧甲氧基-苯基）-2-甲氧 基-丙酸乙酯（製備物3、步驟2)與2-(4-溴基-苯基）-乙胺製備 ，以生產無色油。C20H22BrNO5 [M+H]+之MS (ES) : 437。 實例107 (2S)-2-甲氧基-3-(4-{[(莕-1-基甲基）-胺甲醯基]-甲氧基卜苯 85504.doc -111 - 200406371 基:l·丙酸The title compound is used to prepare (2S, 1R) -2 · ethoxy-3- (4 · {1_ [2- (4_phenoxy-phenyl) _ethylaminomethylamidoethoxy} Phenyl) _propionic acid (Example 1, step 3) The same method was used (2S) -3- (4-carboxymethoxy-phenyl) -2-methoxy-propionic acid ethyl ester (Preparation 3, Step 2) Preparation with 2- (4-bromo-phenyl) -ethylamine to produce a colorless oil. MS (ES) for C20H22BrNO5 [M + H] +: 437. Example 107 (2S) -2-methoxy-3- (4-{[(fluoren-1-ylmethyl) -aminomethylmethyl] -methoxybenzyl 85504.doc -111-200406371 group: l · Propionic acid

對掌體 標題化合物係經由用以製備（2S，1R)_2_乙氧基_3_(4_〇_ [2 (4表氧基-丰基）_乙基胺甲酸基]_乙氧基丨苯基）_丙酸（實 例1、步騾3)之相同方法由（2S)-3-(4-羧甲氧基-苯基）_2_甲氧_ 基-丙酸乙_：Γ(製備物3、步驟2)與C-莕-1-基-甲胺製備，以生j 產無色油。C23H23N05 [M+H]+之 MS (ES) : 394 〇 實例108 (2^_3_(4_{[2_(2,6-二氯基-芊巯基）_乙基胺甲醯基]_甲氧基} -苯基）-2 -甲氧基-丙酸The title compound of palmar is used to prepare (2S, 1R) _2_ethoxy_3_ (4_〇_ [2 (4-epioxy-fungyl) _ethyl carbamate] _ethoxy 丨Phenyl) _propionic acid (Example 1, step 3) The same method was prepared from (2S) -3- (4-carboxymethoxy-phenyl) _2_methoxy_yl-propionic acid ethyl_: Γ ( Preparation 3, step 2) and C-fluoren-1-yl-methylamine to produce colorless oil. C23H23N05 [M + H] + MS (ES): 394 〇 Example 108 (2 ^ _3_ (4 _ {[2_ (2,6-dichloro-fluorenylthio) _ethylaminomethylmethyl) _methoxy } -Phenyl) -2 -methoxy-propionic acid

標題化合物係經由用以製備（2S，lR)-2_乙氧基-3·(4-{1-[2-(4_苯氧基-苯基）·乙基胺甲醯基]-乙氧基}苯基）-丙酸（實 例1、步騾3)&lt;相同方法由（2S»(仁羧甲氧基-苯基）_2_甲氧 基-丙酸乙酯（製備物3、步驟2)與匕莕-丨-基·甲胺製備，以生 產黃色油。C21H23Cl2N〇5s [M+H疒之MS (ES) : 473。 實例109 (2S)-3-(4-{[苄基_(1_苯基_乙基）·胺甲醯基]•甲氧基卜苯基） 85504.doc .. _ 200406371 -2-甲氧基-丙酸The title compound is used to prepare (2S, 1R) -2_ethoxy-3 · (4- {1- [2- (4-phenoxy-phenyl) · ethylaminomethylmethyl] -ethyl Oxy} phenyl) -propionic acid (Example 1, step 骡 3) &lt; The same method was used (2S »(rencarboxymethoxy-phenyl) _2_methoxy-propionic acid ethyl ester (Preparation 3, Step 2) Preparation with d-methyl-methylamine to produce yellow oil. C21H23Cl2N05s [M + H 疒 MS (ES): 473. Example 109 (2S) -3- (4-{[Benzyl _ (1_phenyl_ethyl) · carbamoyl] · methoxyphenyl) 85504.doc .. _ 200406371 -2-methoxy-propionic acid

核越化合物係經由用以製備（2S，1R)_2•乙氧基_3_㈠ [2-(4-苯氧基-苯基）_乙基胺甲醯基]_乙氧基丨苯基丙酸（實 例1、步騾3)之相同方法、由（2S)-3气‘羧甲氧基_苯基）_2_甲氧^ 基-丙酸乙酉製備物3、步驟2)與（1_苯基-乙基）_(2_乙烯基-兰 己_2,4_一晞^ 胺製備，以生產無色油。c”H29N〇5 [m+h]+ 之 MS (ES) : 448 〇 實例110 (2S)-3-(4-{2-[4|乙醯基_苯基）十井小基]_2_氧基乙氧基卜 苯基）-2 -甲氧基-丙酸 對掌體The nuclear compound is used to prepare (2S, 1R) _2 • ethoxy_3_fluorene [2- (4-phenoxy-phenyl) _ethylaminomethylmethyl] _ethoxy 丨 phenylpropionic acid (Example 1, step 3) The same method as in (2S) -3Gas'carboxymethoxy_phenyl) _2_methoxy ^ ethyl-propionate preparation 3, step 2) and (1-benzene -Ethyl) _ (2_vinyl-lanhex-2,4_monofluorene) amine to produce a colorless oil. C "H29N〇5 [m + h] + MS (ES): 448 〇 Example 110 (2S) -3- (4- {2- [4 | Ethylfluorenyl_phenyl) decyl small base] _2_oxyethoxyphenylphenyl) -2 -methoxy-propionic acid body

褕通化合物係經由用以製備（2S, 1R)_2_乙氧基·3兴4_〇_ [2-(4-苯氧基-苯基）_乙基胺甲酿基]-乙氧基}苯基）丙酸（實 m、步驟3)之相同方法由（2S)_3·(續甲氧基_苯基）-2•甲氧 基-丙酸乙酷（製備物3、步驟2mi_(4十井]备苯基）·乙嗣 I備，以生產拱色油。C24h28n2〇6 [m+H]+之MS (ES) : 441。 實例111 85504.doc -113- (2S)-2·甲氧基_3_{4·[2_氧基_2_(4•對-甲苯基 氧基l·苯基}_丙酸 對掌體A compound is used to prepare (2S, 1R) _2_ethoxy · 3Xing 4_〇_ [2- (4-phenoxy-phenyl) _ethylaminomethyl] -ethoxy } Phenyl) propanoic acid (real m, step 3) The same method is obtained from (2S) _3. 4Ten well] prepared phenyl) · acetamidine to prepare arch oil. C24h28n2 06 [m + H] + MS (ES): 441. Example 111 85504.doc -113- (2S) -2 · Methoxy_3_ {4 · [2_oxy_2_ (4 • p-tolyloxyl · phenyl} _propionic acid palmate

‘通化合物係經由用以製備（2s，iR)_2•乙氧基卜 [2-(4·冬乳基笨基）_乙基胺甲酸基]•乙氧基}苯基丙酸（實 例卜步驟3)^相同方法由（2s)-3♦叛甲氧基-苯基α〒氧 基-丙酸乙酿（製備物3、步驟2mi|甲苯基♦井製備，以 生產 κ 色油。C23H28N205 [M+H]+之 MS (ES) : 413。 實例112 (S) 3 (4 {[乙基_(2_氟基_节基）_胺甲酸基]-〒氧基丨_苯基） -2-甲氧基-丙酸The general compound is used to prepare (2s, iR) _2 • ethoxyb [2- (4 · winter lactylbenzyl) _ethyl carbamate] • ethoxy} phenylpropanoic acid (example b Step 3) ^ The same method is prepared from (2s) -3. MS (ES) of [M + H] +: 413. Example 112 (S) 3 (4 [[Ethyl_ (2_fluoro group_benzyl) _carbamic acid group] -fluorenoxy 丨 _phenyl) -2-methoxy-propionic acid

〇 f 標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4-{l-[2-(4-苯氧基-苯基）_乙基胺甲醯基]_乙氧基丨苯基）_丙酸（實 例1、步驟3)之相同方法由（2S)-3_(4-羧甲氧基-苯基甲氧 基-丙酸乙酯（製備物3、步騾2)與乙基_(2_氟基_苄基）_胺製備 ，以生產無色油。C21H24FN〇5 [M+H]+之MS (ES) : 390。 實例113 (2S)-3-(4-{[乙基_(3•甲基_苄基兴胺甲醯基]_甲氧基卜苯基） 85504.doc -114- 200406371 -2 -甲乳基-丙酸〇f The title compound is used to prepare (2S, 1R) -2-ethoxy-3- (4- {l- [2- (4-phenoxy-phenyl) -ethylaminomethylmethyl] _Ethoxy 丨 phenyl) _propionic acid (Example 1, step 3) The same method was prepared from (2S) -3_ (4-carboxymethoxy-phenylmethoxy-propionic acid ethyl ester (Preparation 3, Step 2) Preparation with ethyl_ (2-fluoro_benzyl) _amine to produce a colorless oil. MS (ES) of C21H24FN05 [M + H] +: 390. Example 113 (2S) -3 -(4-{[ethyl_ (3 • methyl_benzylmethylaminomethyl) _methoxyphenyl) 85504.doc -114- 200406371 -2 -methyllactyl-propionic acid

對掌體 標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4_{l-[2(冬氧基本基）·乙基胺甲醯基]-乙氧基}苯基）_丙酸（實 例1、步騾3)之相同方法由（2S)-3-(4-羧甲氧基-苯基）-2_甲氧 基-丙酸乙酯（製備物3、步騾2)與乙基-(3-甲基-苄基胺製備 ’以生產無叁油。C22H27N〇5 [M+H]+之MS (ES) : 386。 —^、 :、 實例114 (2S)_3_(4_{2_[4-(‘氟基-苄基）-哌畊-1·基]-2-氧基-乙氧基卜 苯基）-2·甲氧基-丙酸The title compound of palmar is used to prepare (2S, lR) -2-ethoxy-3- (4_ {l- [2 (winteroxybenzyl) · ethylaminomethyl}]-ethoxy} Phenyl) _propionic acid (Example 1, step 3) The same method as (2S) -3- (4-carboxymethoxy-phenyl) -2_methoxy-propionic acid ethyl ester (Preparation 3 Step 2) Preparation with ethyl- (3-methyl-benzylamine 'to produce tri-free oil. MS (ES) of C22H27N05 [M + H] +: 386. ^,:, Example 114 (2S) _3_ (4_ {2_ [4-('Fluoro-benzyl) -pigen-1 · yl] -2-oxy-ethoxyphenylphenyl) -2 · methoxy-propionic acid

對掌體 〇 標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4-{κ [2-(4_苯氧基^苯基）-乙基胺甲醯基]•乙氧基}苯基）-丙酸（實 例1、步驟3)之相同方法由（2S)-3_(4-羧甲氧基-苯基）-2-甲氣 基-丙酸乙酯（製備物3、步驟2)與1_(4_氟基_苄基）_哌畊製備 ，以生產無色油。C23H27FN2〇5 [m+H]+之 MS (ES) : 431。 實例115 (2S)-3-{4-[(6-氟基_苯并噻唑_2_基胺甲醯基）_甲氧基]_苯基} -2-甲氧基_丙酸 85504.doc -115- 200406371The title compound is used to prepare (2S, 1R) -2-ethoxy-3- (4- {κ [2- (4-phenoxy ^ phenyl) -ethylaminomethyl) ] • ethoxy} phenyl) -propionic acid (Example 1, step 3) The same method was used (2S) -3_ (4-carboxymethoxy-phenyl) -2-methylamino-propionic acid ethyl ester (Preparation 3, step 2) and 1- (4-fluoro-benzyl) _piperin to produce a colorless oil. C23H27FN205 [m + H] + MS (ES): 431. Example 115 (2S) -3- {4-[(6-Fluoro_benzothiazole_2_ylaminomethylamidino) _methoxy] _phenyl} -2-methoxy_propionic acid 85504. doc -115- 200406371

以製備（2S， 標題化合物係經由用To prepare (2S, the title compound is

基-丙酸乙酯（製備物3、步驟 lR)-2-乙氧基·3-(4-{1- 備，以生產無色油。 胺甲醯基]•乙氧基}苯基）_丙酸（實 方法由（2S)-3-(4•羧甲氧基-苯基）-2-甲氧 ^ 3、步驟2)與6_氟基-苯并嘧唑_2_基胺製 Ci9H17FN2〇5S [M+H]+之 MS (ES) : 405。 實例116 (2S) 3 (4-{[2-(乙基_間·甲苯基_胺基&gt; 乙基胺甲醯基])_甲氧 基}_苯基）-2_甲氧基-丙酸-Ethyl propionate (Preparation 3, Step 1R) -2-ethoxy · 3- (4- {1- Preparation, to produce a colorless oil. Carbamate] • ethoxy} phenyl) _ Propionic acid (actual method is prepared from (2S) -3- (4 • carboxymethoxy-phenyl) -2-methoxy ^ 3, step 2) and 6-fluoro-benzopyrazole_2_ylamine MS (ES) for Ci9H17FN205S [M + H] +: 405. Example 116 (2S) 3 (4-{[2- (ethyl_m-tolyl_amino)> ethylaminomethylmethyl]) _ methoxy} _phenyl) -2_methoxy- Propionic acid

標題化龟i务係經由用以製備（2S，lR)-2_乙氧基-3_(4-{1-[2-(4-苯氧基·苯基乙基胺甲醯基 &gt; 乙氧基}苯基）_丙酸（實 例1、步驟3)之相同方法由（2S)_3_(4_羧甲氧基·苯基）_2_甲氧 基-丙酸乙酯（製備物3、步騾2)與N1-乙基-N1-間-甲苯基-乙 烷_1，2_二胺製備，以生產無色油。c23H3〇N205 [M+H]+之MS (ES) : 414 〇 對掌體 實例117 (2S)-2-甲氧基-3-{4-[(2-吡啶-2·基-乙基胺甲醯基）-甲氧基]- 苯基卜丙酸 85504.doc -116- 200406371 對掌體The title is based on the preparation of (2S, lR) -2_ethoxy-3_ (4- {1- [2- (4-phenoxy · phenylethylaminemethylmethyl) &gt; ethyl Oxy} phenyl) _propionic acid (Example 1, step 3) The same method was used (2S) _3_ (4_carboxymethoxy · phenyl) _2_methoxy-propionic acid ethyl ester (Preparation 3, Step 2) Preparation with N1-ethyl-N1-m-tolyl-ethane-1, 2-diamine to produce a colorless oil. C23H3〇N205 [M + H] + MS (ES): 414 Example of palm body 117 (2S) -2-methoxy-3- {4-[(2-pyridin-2.yl-ethylaminomethylamidino) -methoxy] -phenylpropanoic acid 85504. doc -116- 200406371 pair of palms

秫心化口物係經由用以製備（2S，1R)_2-乙氧基-3-(4-{l-[2_(心耗基’基）-乙基胺甲酸基l·乙氧基}苯基）-丙酸（實 例1 ^驟3)〈相同方法由（2S)-3-(4-叛甲氧基·苯基）·2-甲氧 基丙酸乙酉曰（製備物3、、步驟2)與2_咐淀冬基-乙胺製備，以 生產秩色油二 C19h22n2〇5 [M+H]+之MS (ES) : 359。 ' 實例118 (2S) 2甲氧基_3_{‘[(2_吡啶基-乙基胺甲醯基）_甲氧基]_ 苯基}-丙酸Cardiac saccharides are used to prepare (2S, 1R) _2-ethoxy-3- (4- {l- [2_ (cardiacyl'yl) -ethylcarbamic acid l · ethoxy} Phenyl) -propionic acid (Example 1 ^ Step 3) <The same method was used (2S) -3- (4-Retmethoxy · phenyl) · 2-methoxypropanoic acid ethyl ester (Preparation 3 ,, Step 2) Preparation of Diandongji-Ethylamine to produce MS (ES): 359 of C19h22n205 [M + H] +. '' Example 118 (2S) 2methoxy_3 _ {’[(2_pyridyl-ethylaminomethyl) _methoxy] _phenyl} -propionic acid

標題化合勒係經由用以製備（2S，lR)-2-乙氧基-3·(4-{1-[2-(4-苯氧基-苯基）_乙基胺甲醯基]-乙氧基丨苯基丙酸（實 例1、步驟3)之相同方法由（2S)-3-(4_羧甲氧基-苯基）-2-甲氧 基—丙酸乙酯（製備物3、步驟2)與2-吡啶-3-基-乙胺製備，以 生產無色油。C19H22N205 [M+H]+之MS (ES) : 359。 實例119 (2S)-E-3-{4-[(4-第三-丁基·環己基胺甲醯基兴甲氧基卜苯基} -2-甲氧基-丙酸 85504.doc -117- 200406371The title compound was used to prepare (2S, lR) -2-ethoxy-3 · (4- {1- [2- (4-phenoxy-phenyl) _ethylaminomethylmethyl]- The same method for ethoxy 丨 phenylpropionic acid (Example 1, step 3) was prepared from (2S) -3- (4-carboxymethoxy-phenyl) -2-methoxy-propionic acid ethyl ester (preparation 3. Step 2) Preparation with 2-pyridin-3-yl-ethylamine to produce colorless oil. MS (ES) of C19H22N205 [M + H] +: 359. Example 119 (2S) -E-3- {4 -[(4-Third-butyl-cyclohexylaminemethylamidoxylmethoxyphenyl)}-2-methoxy-propionic acid 85504.doc -117- 200406371

標題化合物係經由用以製備（2S，1R)-2_乙氧基_3_(4_丨1_ 、 對掌體 [2-(4-苯氧基-苯基）_乙基胺甲醯基p乙氧基丨苯基）_丙酸（實 例卜步驟3)之相同方法由（2S)-3-(4-羧甲氧基-苯基）-2-甲氧 基-丙酸乙酯（製備物3、步驟2)與E_4-第三_丁基-環己胺製備 ’以生產典色油。C22H33N05 [M+H]+之MS (ES) : 392。 實例120 (2S)-Z-3-{4-[(4-第三_丁基_環己基胺甲醯基)_甲氧基]_笨基} _2_甲氧基-丙酸The title compound is used to prepare (2S, 1R) -2_ethoxy_3_ (4_ 丨 1_), p-body [2- (4-phenoxy-phenyl) _ethylaminomethylmethyl p The same method of ethoxy 丨 phenyl) _propionic acid (Example 3 step 3) was prepared from (2S) -3- (4-carboxymethoxy-phenyl) -2-methoxy-propionic acid ethyl ester ( Preparation 3, step 2) and E_4-Third-butyl-cyclohexylamine were prepared to produce a typical color oil. MS (ES) for C22H33N05 [M + H] +: 392. Example 120 (2S) -Z-3- {4-[(4-Third-butyl_cyclohexylaminemethylamidino) _methoxy] _benzyl} _2_methoxy-propionic acid

對掌體 標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4-{1-[2-(4-苯氧苯基）_乙基胺甲醯基乙氧基}苯基）_丙酸（實 例1、步驟3)之相同方法由（2S)-3-(4-羧甲氧基-苯基）-2·甲氧 基-丙酸乙酿(製備物3、步驟2)與Z-4-第三-丁基-環己胺製備 ’以生產無色油。C22H33N05 [M+H]+之MS (ES) ·· 392。 實例121 (2S)-3-(4-環丁胺甲醯基甲氧基-苯基）-2_甲氧基-丙酸The title compound of the palmate was used to prepare (2S, 1R) -2-ethoxy-3- (4- {1- [2- (4-phenoxyphenyl) _ethylaminemethylamidoethoxy Group} phenyl) _propionic acid (Example 1, step 3) The same method was prepared from (2S) -3- (4-carboxymethoxy-phenyl) -2 · methoxy-propionic acid (preparation 3. Step 2) Preparation with Z-4-third-butyl-cyclohexylamine 'to produce a colorless oil. MS (ES) of C22H33N05 [M + H] + · 392. Example 121 (2S) -3- (4-Cyclobutylaminemethylmethoxy-phenyl) -2-methoxy-propionic acid

85504.doc -118- 200406371 標題化合物係經由用以製備（2S，乙氧基_3_(4_^ 〇(4-苯氧基二苯基）-乙基胺甲醯基卜乙氧基}苯基丙酸（實 m、步驟3)之相同方法由（2S)i(4邊甲氧基苯基甲氧 基-丙酸乙酯（製備物3、步驟2)與環丁胺製備，以生產無色 油。C16H21N05 [Μ-ΗΓ之MS (ES) : 306。 實例122 (2S)_3-{4-[(l，3-二甲基_丁基胺甲醯基）·甲氧基卜苯基卜孓甲 氧基-丙酸85504.doc -118- 200406371 The title compound was used to prepare (2S, ethoxy_3_ (4_ ^ 〇 (4-phenoxydiphenyl) -ethylaminomethylamidoethoxy) phenyl The same method for propionic acid (solid m, step 3) was prepared from (2S) i (4-side methoxyphenylmethoxy-ethyl propionate (preparation 3, step 2) and cyclobutylamine) to produce colorless Oil. C16H21N05 [MS (ES) of Μ-ΗΓ: 306. Example 122 (2S) _3- {4-[(l, 3-dimethyl-butylaminomethylmethyl) · methoxyphenylphenyl孓 methoxy-propionic acid

對掌體 標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4_{i_ [2-(4-苯氧基-苯基）_乙基胺甲醯基μ乙氧基丨苯基）_丙酸（實 例1、步驟3)之相同方法由（2S)-3-(4-羧甲氧基-苯基）-2-甲氧 基，丙酸乙製備物3、步驟2)與1，3-二甲基-丁胺製備，以 生產無色油 一。C18H27N05 [Μ_ΗΓ之 MS (ES) : 336。 實例123 (2S)-2·甲氧基_3_{4_[(1_甲基-己基胺甲醯基&gt; 甲氧 基]-苯基卜丙酸The title compound of the palmate was used to prepare (2S, 1R) -2-ethoxy-3- (4_ {i_ [2- (4-phenoxy-phenyl) _ethylaminomethylethyl) ethyl Oxy 丨 phenyl) _propionic acid (Example 1, step 3) The same method was prepared from (2S) -3- (4-carboxymethoxy-phenyl) -2-methoxy, ethyl propionate 3 Step 2) Preparation with 1,3-dimethyl-butylamine to produce a colorless oil. C18H27N05 [MS of MS (ES): 336. Example 123 (2S) -2 · methoxy_3_ {4 _ [(1_methyl-hexylaminemethylamidino &gt; methoxy) -phenylpropanoic acid

85504.doc -119- 200406371 標題化合物係經由用以製備（2S，乙氧基(扣{1-[2-(4-苯氧基二苯基）_乙基胺甲醯基卜乙氧基}苯基卜丙酸（實 例1、步驟3)之相同方法由（2s)_3-(4—羧甲氧基-苯基）_2_甲氧 基-丙酸乙酯（製備物3、步驟2)與丨_甲基_己胺製備，以生產 典色油。CwHmNOs [M-Η]-之 MS (ES) : 350。 實例124 (2S)-2-甲氧基-3-{4-[(l-甲基-丁基胺甲醯基）_甲氧 基]-苯基}-丙酸85504.doc -119- 200406371 The title compound was prepared via (2S, ethoxy ({{[[2- (4-phenoxydiphenyl) _ethylaminemethylamidoethoxy] The same method for phenylpropionic acid (Example 1, step 3) consists of (2s) _3- (4-carboxymethoxy-phenyl) _2_methoxy-propionic acid ethyl ester (Preparation 3, step 2) And 丨 _methyl_hexylamine to produce a typical color oil. MS (ES) of CwHmNOs [M-Η]-: 350. Example 124 (2S) -2-methoxy-3- {4-[( l-methyl-butylaminomethyl) -methoxy] -phenyl} -propionic acid

標題化合物係經由用以製備（2S，乙氧基_3_{1-[2-(4-苯氧基-苯基）_乙基胺甲醯基乙氧基}苯基）_丙酸（實 例1、步驟3)之相同方法由（2S)冬⑷羧甲氧基-苯基甲氧 基-丙酸乙酯（製備物3、步驟2)與1-甲基-丁胺製備，以生產 無色油。CiTHuNOs [M_H]-之MS (ES) : 322。 實例125 (2S)-2·甲氧基_3·{4_[(3_甲基-丁基胺甲醯基）_甲氧 基]-苯基}-丙酸 〇 ΗΟThe title compound was prepared via (2S, ethoxy_3_ {1- [2- (4-phenoxy-phenyl) _ethylaminemethylamidoethoxy} phenyl) _propionic acid (Example 1. The same method as in step 3) is prepared from (2S) winter carboxymethyl-phenylmethoxy-propionic acid ethyl ester (preparation 3, step 2) and 1-methyl-butylamine to produce colorless oil. CiTHuNOs [M_H] -MS (ES): 322. Example 125 (2S) -2 · methoxy_3 · {4 _ [(3-methyl-butylaminemethylamidino) _methoxy] -phenyl} -propionic acid 〇 ΗΟ

對掌體 〇 85504.doc -120- 200406371 標題化合物係經由用以製備（2S，1R)-2-乙氧基-3-(4-{1-[2-(4-苯氧基^笨基）_乙基胺甲醯基乙氧基}苯基）_丙酸（實 ^ 例1、步騾3)之相同方法由（28)_3_(4_羧甲氧基-苯基甲氧 · 基-丙酸乙酯（製備物3、步驟2)與3-甲基-丁胺製備，以生產 無色油。C17H25N〇5 [M-Η]-之MS (ES) : 322。 實例126 (2S)-3-(4_環戊基胺甲醯甲氧基_苯基）-2_甲氧基_丙酸 標題化合物係經由用，以製備（2S，1R)-2_乙氧基^(4-0-[2-(4-苯氧^一-苯基）_乙基胺甲醯基乙氧基丨苯基）_丙酸（實 $ 例1、步驟3)之〜相同方法由（2S)-3-(4-羧甲氧基-苯基）-2-甲氧 基-丙酸乙酯（製備物3、步驟2)與環戊胺製備，以生產無色 油。C17H23N05 [Μ-ΗΓ之 MS (ES) : 320。 實例127 (2S)-2-甲氧基-3_{4-[(l-甲基-3-苯基-丙基胺甲醯基）-甲氧 基l·苯基卜丙酸Counterpart 〇85504.doc -120- 200406371 The title compound is used to prepare (2S, 1R) -2-ethoxy-3- (4- {1- [2- (4-phenoxy ^ benzyl) ) _Ethylaminomethylmethylethoxy} phenyl) _propionic acid (Example 1, step 3) The same method is given by (28) _3_ (4_carboxymethoxy-phenylmethoxy group -Ethyl propionate (Preparation 3, Step 2) and 3-methyl-butylamine to produce a colorless oil. C17H25N05 [M-Η]-MS (ES): 322. Example 126 (2S) -3- (4-Cyclopentylamine formamidinemethoxy_phenyl) -2_methoxy_propionic acid The title compound was used to prepare (2S, 1R) -2_ethoxy ^ (4 -0- [2- (4-phenoxy ^ mono-phenyl) _ethylaminemethylamidoethoxy 丨 phenyl) _propionic acid (Example 1, Step 3) ~ The same method by (2S ) -3- (4-carboxymethoxy-phenyl) -2-methoxy-propionic acid ethyl ester (Preparation 3, Step 2) and cyclopentylamine to produce a colorless oil. C17H23N05 [Μ-ΗΓ MS (ES): 320. Example 127 (2S) -2-methoxy-3_ {4-[(l-methyl-3-phenyl-propylaminomethylmethyl) -methoxyl · benzene Glyproic acid

標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4-{1-[2-(4-苯氧基·苯基）_乙基胺甲醯基乙氧基}苯基丙酸（實 例1、步驟3)之相同方法由（2S)-3-(4-羧甲氧基_苯基）_2-甲氧 基·丙酸乙醋（製備物3、步騾2)與1-甲基-3-苯基-丙胺製備， 以生產無色油。C22H27N05 [Μ-ΗΓ之MS (ES) : 384。 實例128 85504.doc -121- 200406371The title compound is used to prepare (2S, lR) -2-ethoxy-3- (4- {1- [2- (4-phenoxy · phenyl) _ethylaminemethylamidoethoxy } The same method for phenylpropionic acid (Example 1, step 3) was made from (2S) -3- (4-carboxymethoxy_phenyl) _2-methoxy · ethyl propionate (Preparation 3, Step 骡) 2) Prepared with 1-methyl-3-phenyl-propylamine to produce a colorless oil. C22H27N05 [MS (ES) of Μ-ΗΓ: 384. Example 128 85504.doc -121- 200406371

(23)-3-{4-[(2,2,3,3,4,4,4-七氟基-丁基胺甲醯基）_甲氧基&gt; 苯基甲氧基-丙酸(23) -3- {4-[(2,2,3,3,4,4,4-heptafluoro-butylaminomethylmethyl) _methoxy &gt; phenylmethoxy-propionic acid

標題化合物係經由用以製備（2S，lR)-2-乙氧基_3_(4·{κ [2-(4-苯氧基-苯基）_乙基胺甲醯基卜乙氧基丨苯基）_丙酸（實 例1、步騾3)之相同方法由（2S)-3_(‘羧甲氧基_苯基）_2_甲氧 —The title compound is used to prepare (2S, lR) -2-ethoxy_3_ (4 · {κ [2- (4-phenoxy-phenyl) _ethylaminemethylmethylethoxy) The same method for phenyl) _propionic acid (Example 1, step 3) is (2S) -3 _ ('carboxymethoxy_phenyl) _2_methoxy—

基-丙酸乙gK製備物3、步騾2)與九氟丁胺製備，以生產無P 色油。C16H16F、7N〇5 [Μ-ΗΓ之 MS (ES) : 434。 實例129 (2S)-3-{4-[(5-第三丁基塞二吃·2_基胺甲酿基）·甲氧 基]-苯基}_2_甲氧基-丙酸Ethyl-propionate gK preparation 3, step 2) and nonafluorobutylamine to produce P-free color oil. C16H16F, 7N05 [MS-ES (MS): 434. Example 129 (2S) -3- {4-[(5-Third-butyl succinyl-2-methylaminomethyl) · methoxy] -phenyl} _2_methoxy-propionic acid

標題化合物係經由用以製備（2S，lR)-2_乙氧基-3-(4-{1- [2-(4-苯氧基-苯基&gt; 乙基胺甲醯基]_乙氧基丨苯基丙酸（實 例1、步驟3)之相同方法由（2S)-3-(4-叛甲氧基-苯基）_2甲氧 基-丙酸乙酿（製備物3、步驟2)與5-第三-丁基-[1，3,仆塞二也 -2-基胺製備’以生產無色油。a此3N3〇5S [M_町之MS (ES) :392 ° 實例130 85504.doc -122- 200406371 (2S)-3-Μ-「ί5·笛一 吊二·丁基-n，3,4l·塞二唑_2_基胺甲醯基）-甲氧 、 基]-苯基}-2-甲氧基-丙酸The title compound is used to prepare (2S, lR) -2-ethoxy-3- (4- {1- [2- (4-phenoxy-phenyl>) ethylaminomethyl] -ethyl The same method for oxy 丨 phenylpropionic acid (Example 1, Step 3) was prepared from (2S) -3- (4-Retmethoxy-phenyl) _2methoxy-propionic acid (Preparation 3, Step 2) Prepared with 5-tert-butyl- [1,3, bis-di-2-ylamine 'to produce a colorless oil. A 3N3〇5S [M_machi's MS (ES): 392 ° Example 130 85504.doc -122- 200406371 (2S) -3-M- 「ί5 · Diyihang di · Butyl-n, 3,4l · Sediazole-2-methylaminomethylmethyl） -methoxy, ] -Phenyl} -2-methoxy-propionic acid

心通化合物係經由用以製備（2s，iR)_2_乙氧基 [2-(4-苯氧基.苯基）·乙基胺甲醯基]•乙氧基}苯基）_丙酸（實 m m 相同方法由（2S)_3_(4_叛甲氧基·苯基）冬甲氧 基_丙酸乙m製備物3、步驟2)與5_第三丁基·π,3观二唾 基胺製備以生產無色油。CuH23n3〇5S [M—Hj-之MS (ES) :392。 實例13 1 (2S) 3 {4·[(4-第二.丁基巧塞唆基胺甲酸基）_甲氧基卜苯基} •2-甲氧基_丙酸Xintong compound is used to prepare (2s, iR) _2_ethoxy [2- (4-phenoxy.phenyl) · ethylaminomethylmethyl] • ethoxy} phenyl) _propionic acid (Solid mm, the same method is prepared from (2S) _3_ (4_Retmethoxy · phenyl) winter methoxy_propionic acid ethyl m 3, step 2) and 5_ third butyl, π, 3 Kanji Sialylamine is prepared to produce a colorless oil. CuH23n305S [M-Hj-MS (ES): 392. Example 13 1 (2S) 3 {4 · [(4-Second. Butylchocetinoaminocarbamate) _methoxyphenylphenyl} • 2-methoxy_propionic acid

標題化合物係經由用以製備（2S，叫2-乙氧基·3-(4-{1- [2-(4-冬氧基-笨基）_乙基胺曱酿基]_乙氧基}苯基）_丙酸（實 例1、步驟3)之相同古沐士^0〇、β 祁U万法由（2S)-3_(4-羧甲氧基-苯基）-2_甲氧 基-丙酸乙酿（製備物3 丰 、表1葡物3步驟2)與4-第三-丁基·3Η-114·嘧唑 -2-基胺製備，以生產益多 王座揉色油。C19H24N205S [Μ-ΗΓ之 MS (ES) 85504.doc -123- 200406371 :39卜 實例132 3-{4-[(5_環丙基「 土 _U，3,4]嚯二唑_2·基胺甲醯基）_甲氧基]苯 基卜甲氧基-丙酸The title compound is used to prepare (2S, called 2-ethoxy · 3- (4- {1- [2- (4-asthoxy-benzyl) _ethylamine, alkynyl] _ethoxy } Phenyl) _propionic acid (Example 1, step 3) the same Gu Shi ^ 0〇, β Qi U Wanfa from (2S) -3_ (4-carboxymethoxy-phenyl) -2_methoxy Based on ethyl propionate (Preparation 3, Table 1, Step 3, Step 2) and 4-Third-Butyl · 3Η-114 · Pymidazole-2-ylamine to produce Yido Throne Kneading Oil C19H24N205S [MS (ES) of M-ΜΓ 85504.doc -123- 200406371: 39 Example 132 3- {4-[(5_Cyclopropyl "__U, 3,4] 嚯 Diazole_2 · Aminomethylmethyl) -methoxy] phenylbutoxy-propionic acid

Ο HOΟ HO

對掌體Palm body

標題化合杨作细丄m 〜係t由用以製備（2S，lR)-2_乙氧基-3-(4-{l-[2-(4_苯氧基_装其、 +暴）-乙基胺甲醯基]-乙氧基}苯基）_丙酸（實 例1、步驟3)之相因士、土山 棚冋万法由（2S)-3_(4-羧甲氧基-苯基）·2_甲氧 基丙酸乙醋（製備物3、步驟2)與5_環丙基-Π，3,4Μ二吐·2_ 基胺製備以生產無色油。C17H19N305S [M-Η]-之MS (ES) :376。 實例133 (28)-3^4-己基胺甲醯甲氧基_苯基）_2_甲氧基-丙酸The title compound Yang made fine 丄 m ~ system t is used to prepare (2S, lR) -2_ethoxy-3- (4- {l- [2- (4_phenoxy_zhuangqi, + violet) -B Aminomethylamido] -ethoxy} phenyl) _propionic acid (Example 1, step 3), phase factor, soil mountain shed method (2S) -3_ (4-carboxymethoxy-phenyl ). Ethyl 2-methoxypropionate (Preparation 3, Step 2) was prepared with 5-cyclopropyl-II, 3,4M ditoxamine to produce a colorless oil. C17H19N305S [M-Η] -MS (ES): 376. Example 133 (28) -3 ^ 4-Hexylamine formamidinemethoxy_phenyl) _2_methoxy-propionic acid

標題化合物係經由用以製備（2S，1r)_2_乙氧基-Ή—ρ· [2_(4-苯氧基-苯基）·乙基胺甲醯基乙氧基}苯基）_丙酸（實 例1、步騾3)之相同方法由（2S)|(4-羧甲氧基-苯基卜孓甲氧 基-丙酸乙酯（製備物3、步騾2)與己庚胺製備，以生產無色 油。C18H27N05 [Μ-ΗΓ之MS (ES) : 338。 85504.doc -124- 200406371 實例134 (2S)-3_(右庚基胺甲醯甲氧基·苯基）-2-甲氧基-丙酸The title compound is used to prepare (2S, 1r) _2_ethoxy-Ή-ρ · [2_ (4-phenoxy-phenyl) · ethylaminomethylamidoethoxy} phenyl) _propion The same method for the acid (Example 1, Step 3) was prepared from (2S) | (4-carboxymethoxy-phenylbutanylmethoxy-propionic acid ethyl ester (Preparation 3, Step 2) and heptylamine Prepared to produce a colorless oil. C18H27N05 [MS-ES (M-ΗΓ): 338. 85504.doc -124- 200406371 Example 134 (2S) -3_ (Dexylheptylamine methyl methoxy · phenyl) -2 -Methoxy-propionic acid

標題化合物係經由用以製備（2S，1R)_2_乙氧基_3_(4_{卜 [2-(4-苯氧基·苯基）·乙基胺甲酿基]_乙氧基丨苯基）_丙酸（實 例1步驟3)之相同方法由（2s)-3-(4-羧甲氧基_苯基）_2_甲氧 基·丙酸乙自^製備物3、步驟2)與庚胺製備，以生產無色油 。C19H29N05 之MS (ES) : 352。 實例135 (2δ)-3_{4·[(3’3-:甲基_丁基胺甲酿基）_甲氧基]-苯基卜2-甲 氧基-丙酸The title compound is used to prepare (2S, 1R) _2_ethoxy_3_ (4 _ {[[[(2- (4-phenoxy · phenyl)] ethylaminomethyl]] ethoxy] benzene Group) _propionic acid (Example 3, step 3) The same method from (2s) -3- (4-carboxymethoxy_phenyl) _2_methoxy · propionic acid ethyl ^ Preparation 3, step 2) Prepared with heptylamine to produce a colorless oil. MS (ES) for C19H29N05: 352. Example 135 (2δ) -3_ {4 · [(3′3-: methyl_butylaminemethyl) _methoxy] -phenylbutan-2-methoxy-propionic acid

標題化合物係經由用以製備（2S，1R)-2_乙氧基_3·(4_{ι_ [2-(4-苯氧基-苯基&gt;乙基胺甲醯基卜乙氧基}苯基）_丙酸（實 例1、步驟3)之相同方法由（2S)_3_⑷羧甲氧基-苯基）_2_甲氧 基-丙酸乙酯（製備物3、步驟2)與3,3-二甲基-丁胺所製備， 以生產無色油。C18H27N〇5 [M-Η]·之MS (ES) : 338。 實例136 3-{3-[(4-順式-第三_丁基-環己基胺甲醯基）_甲氧基卜苯基} 85504.doc -125- 200406371 -2-甲氧基-丙酸（異構物The title compound is used to prepare (2S, 1R) -2_ethoxy_3 · (4_ {ι_ [2- (4-phenoxy-phenyl &gt; ethylaminemethylamidoethoxy)} Phenyl) _propionic acid (Example 1, step 3) The same method was used (2S) _3_⑷carboxymethoxy-phenyl) _2_methoxy-propionic acid ethyl ester (preparation 3, step 2) and 3, 3-dimethyl-butylamine is prepared to produce a colorless oil. C18H27N05 [M-Η] MS (ES): 338. Example 136 3- {3-[(4-cis-tertiary-butyl-cyclohexylaminemethylamidino) _methoxyphenylphenyl} 85504.doc -125- 200406371 -2-methoxy-propyl Acid (isomer

標題化合物係經由用以製備（2S，1R)_2_乙氧基-3_(4_{1_ [2-(4-苯氧基-苯基）_乙基胺甲醯基]_乙氧基丨苯基）_丙酸（實 例1、步騾3)之相同方法由3_(3-羧甲氧基_苯基）_2_甲氧基_ 丙酸甲酯（fijt物4、步驟2)與4-順式_第三-丁基-環己胺製備 ’以生產供色油。C22H33N05 [M+H]+之MS (ES) : 392。 實例137 &gt;{3·[(4-反式-第三-丁基·環己基胺甲醯基)_甲氧基]-苯基} -2-甲氧基-丙酸（異構物2)The title compound is used to prepare (2S, 1R) _2_ethoxy-3_ (4_ {1_ [2- (4-phenoxy-phenyl) _ethylaminomethyl}] _ ethoxy 丨 benzene Group) _propionic acid (Example 1, step 3) The same method consists of 3_ (3-carboxymethoxy_phenyl) _2_methoxy_ methyl propionate (fijt product 4, step 2) and 4- Preparation of cis-third-butyl-cyclohexylamine 'to produce a coloring oil. MS (ES) for C22H33N05 [M + H] +: 392. Example 137 &gt; {3 · [(4-trans-Third-butyl · cyclohexylaminemethylamidino) _methoxy] -phenyl} -2-methoxy-propionic acid (isomer 2 )

標題化合物係經由用以製備（2S，1R)_2_乙氧基_3_(4·{1· [2-(4-苯氧基-苯基）_乙基胺甲醯基]•乙氧基}苯基丙酸（實 例1、步驟3)之相同方法由3气弘羧甲氧基_苯基）_2_甲氧基_ 丙酸甲g旨（製備物4、步·驟2)與4-反式-第三_丁基—環己基胺製 備’以生產與色油。C22jj33N〇5 [M+H]^MS ⑽）：392。 實例138 3-(4-庚基胺甲醯甲氧基_苯基）_2_甲氧基_2_甲基_丙酸 85504.doc -126- 標題化合物係經由用以製備（2S，lR)-2-乙氧基-3-(4-{l-[2-(4-苯氧基-苯基）-乙基胺甲酸基]-乙氧基}苯基）-丙酸（實 例1、步驟3)之相同方法由3-(4-羧甲氧基-苯基）_2_甲氧基-2-甲基·丙酸甲酯與庚胺製備，以生產無色油。c2〇h31no5 [M+H] +之 MS (ES) : 366\〇 _ 生物分析 ' 鼓Jl與共轉感染研旁 化合物在活體外之調節PPARa與PPARy受體之能力，係經 下文詳述之方法決定。DNA依賴性結合（ABCD結合）係利用 SPA科技、以PPAR受體進行。經氮_標定之ppARa與ρρΑΙΙγ 激動劑’係用以做為與本發明化合物產生置換曲線與IC5〇 值之放射性配位體。共轉感染分析係於CV-1細胞進行。報 導者質體含醯基CoA氧化酶（ΑΟχ) PPRE與虫螢光素酶報導 者cDNA上游_^TK啟動子。適當類之ppAR與RXRc^利用含 CMV之啟動子進行組成性表現。對於PPARa與ρΡΑΚβ而言 ，會受CV-1細胞之内生性ΡΡΑΚγ干擾是一個問題。為消減 此干擾，我們使用其中該經轉感染之PPAR之DNA結合區域 係經GAL4者所取代、而GAL4反應單元係用於取代AOX PPRE之GAL4嵌合系統。共轉感染之效率係以相對之ppARa 激動劑與ΡΡΑΙΙγ激動劑參考分子來決定。效率係利用配合濃 度-反應曲線，或在某些情形為單一高濃度激動劑（1〇微莫耳 85504.doc -127- 200406371The title compound is used to prepare (2S, 1R) _2_ethoxy_3_ (4 · {1 · [2- (4-phenoxy-phenyl) _ethylaminomethylmethyl]] ethoxy } The same method for phenylpropionic acid (Example 1, Step 3) consists of 3 carboxymethyl methoxy_phenyl) _2_methoxy_ methyl propionate (Preparation 4, Step 2) and 4 -Trans-Third-Butyl-Cyclohexylamine Preparation 'to produce with color oil. C22jj33N05 [M + H] ^ MS ii): 392. Example 138 3- (4-Heptylamine formamidinemethoxy_phenyl) _2_methoxy_2_methyl_propionic acid 85504.doc -126- The title compound was prepared via (2S, lR) -2-ethoxy-3- (4- {l- [2- (4-phenoxy-phenyl) -ethylcarbamate] -ethoxy} phenyl) -propionic acid (Example 1, The same method of step 3) was prepared from 3- (4-carboxymethoxy-phenyl) -2-methoxy-2-methyl-propionate and heptylamine to produce a colorless oil. c2〇h31no5 [M + H] + MS (ES): 366 \ 〇_ Bioanalysis' The ability of J1 and co-transfected parasite compounds to modulate PPARa and PPARy receptors in vitro is described in detail below Method decision. DNA-dependent binding (ABCD binding) is performed using SPA technology with PPAR receptors. Nitrogen-calibrated ppARa and ρρΑΙΙγ agonists' are used as radioactive ligands that generate displacement curves and IC50 values with the compounds of the invention. Co-transfection analysis was performed on CV-1 cells. The reporter's plastids contain fluorenyl CoA oxidase (ΑΟχ) PPRE and luciferase reporter cDNA upstream ^ TK promoter. Appropriate classes of ppAR and RXRc ^ use CMV-containing promoters for constitutive expression. It is a problem for PPARa and ρΡΑΚβ to be endogenously interfered with by CV-1 cells. To mitigate this interference, we used a GAL4 chimeric system in which the DNA-binding region of the transfected PPAR was replaced by GAL4, and the GAL4 response unit was used to replace AOX PPRE. The efficiency of co-transfection is determined by relative ppARa agonist and PPAIIII agonist reference molecules. Efficiency is based on the combination concentration-response curve, or in some cases a single high concentration agonist (10 micromolar 85504.doc -127- 200406371

濃度）之電腦來決定。對於非PPAR類之受體之結合或共轉感 染研究而言^係使用該特別受體之適當配位體、受體、報 導者建構物等等進行類似分析。 進行這些研究係在評估本發明化合物結合與/或活化不 同細胞核轉錄因子，特別是huPPARa (“hu”意指‘‘人類，，）與 ΙηιΡΡΑΙΙγ之能力。這些研究提供關於本發明化合物之效率與 選擇性之活體外資料。甚且，將本發明化合物之結合與/或 共轉感染資料與作用；^ huPPARa或huPPARy之市售化合物 之資料進行^比較。 將本發明代表性化合物之結合與/或共轉感染資料與參 考者之資料進行比較，以決定結合情形。 對可用以調節PPARa受體之本發明化合物而言，其結合 與共轉感染效率值分別為約&lt;100毫微莫耳濃度，並&gt;5〇%。 當需要共激動劑調節劑時，可將該值在r或另一種所需之 PPAR受體亞型之選擇性間取得平衡。Concentration). For binding or co-transfection studies of non-PPAR receptors, similar analysis is performed using appropriate ligands, receptors, reporter constructs, etc. of the particular receptor. These studies were performed in order to evaluate the ability of the compounds of the invention to bind and / or activate different nuclear transcription factors, particularly huPPARa ("hu" means' 'human,'), and ΙΡΡΑΙΙγ. These studies provide in vitro information on the efficiency and selectivity of the compounds of the invention. Furthermore, the combination and / or co-transfection data and effects of the compounds of the present invention are compared; the data of commercially available compounds of huPPARa or huPPARy are compared. The binding and / or co-transfection data of representative compounds of the present invention are compared with those of the reference to determine the binding situation. For compounds of the present invention that can be used to modulate the PPARa receptor, the values of binding and co-transfection efficiency are about &lt; 100 nanomolar concentration, respectively, &gt; 50%. When a co-agonist modulator is needed, this value can be balanced between r or the selectivity of another desired PPAR receptor subtype.

對於Huapg^I基因轉殖小鼠之三甘油脂減低輿HDLB詹闳醇 升高之評估 為評估本發明化合物對於人類apoAI小鼠之HDL與三甘 油脂含量之效果，共進行17種不同系列之研究。對每個受 測之化合物，皆令7-8週大之經人類apoAI基因轉殖之雄小 鼠（例如，C57BL/6-tgn(apoal)lrub，Jackson Laboratory，Bar Harbor，ME)在個別之籠子中適應環境達兩週，並提供標準 之膳食與無限制之飲水。適應環境後，將小鼠與食物稱重 ，並根據體重隨機分成受測組（n=5)。利用29容量（gauge)、 85504.doc -128- 200406371Evaluation of Triglyceride Reduction in Huapg ^ I Transgenic Mice Reduced HDLB and Zinc Glycol Content To evaluate the effect of the compounds of the present invention on the HDL and triglyceride content of human apoAI mice, a total of 17 different series were performed. the study. For each compound tested, 7-8 week old male mice (eg, C57BL / 6-tgn (apoal) lrub, Jackson Laboratory, Bar Harbor, ME) transfected with human apoAI genes were placed in individual cages. China adapts to the environment for two weeks and provides standard meals and unlimited drinking water. After adapting to the environment, the mice and food were weighed and randomly divided into test groups according to body weight (n = 5). Utilize 29 capacity, 85504.doc -128- 200406371

1-1/2吋彎曲之餵食針每天經口灌食給小鼠共8天劑量。對照 組、受測化合物與正對照組所用之載體為含0.25%吐溫80 (重量/體積）之1%羧甲基纖維素（重量/體積）。所有小鼠每天 接受劑量時間為午前6〜8點，劑量體積為0.2毫升。終止前 ，將動物與膳時秤重，並計算體重改變與消耗之食物。最 後劑量後3小時，以C02讓小鼠安樂死並由心臟穿刺取出血 液（0.5〜1.0毫升）。殺死小鼠後，將其肝、心與副睪之脂肪 塊切出並秤重。讓血液凝固，並藉離心使血清與血液分離。 利用色差岁、藉市售之製備試劑（例如，分別可由Sigma #339-1000與Roche #450061取得三甘油脂與膽固醇）測定膽A 1-1 / 2 inch curved feeding needle was orally administered daily to mice for a total of 8 days. The vehicle used in the control group, the test compound and the positive control group was 1% carboxymethyl cellulose (w / v) containing 0.25% Tween 80 (w / v). All mice received a daily dose of 6-8 o'clock in the morning with a dose volume of 0.2 ml. Before termination, the animals were weighed with meals, and the weight changes and food consumed were calculated. Three hours after the final dose, the mice were euthanized with C02 and blood (0.5 to 1.0 ml) was removed by cardiac puncture. After the mice were killed, the liver, heart, and epiphyseal fat pieces were cut out and weighed. Allow the blood to clot and separate the serum from the blood by centrifugation. Color difference is measured using commercially available preparation reagents (for example, triglyceride and cholesterol can be obtained from Sigma # 339-1000 and Roche # 450061, respectively).

固醇與三甘油脂。該方法係由發表之研究（參照，McGowan M. W.等人·，Clin Chem 29:538-542, 1983; Allain C. C·等人 Clin Chem 20:470-475, 1974)所作之修正。市售之分別的標 準三甘油脂與總膽固醇、市售品質之對照組血漿與樣本皆 利用200微升試劑進行二重複測定。將另一等份之樣本加入 含200微升水中，提供每個樣本之空白對照。令培養盤於培 養盤震動氣:Lt溫下保溫，並分別以500 nm與540 nm測定 總膽固醇與三甘油脂。正對照組之值皆落於預定範圍，而 且樣本變異之係數皆在10%以下。同時分析每個實驗之所有 樣本，以將各分析間之變異降至最低。 分離血清脂蛋白，並藉偶合於主機控制之偵測系統之快 速蛋白質液相層析（FPLC)定量膽固醇。膽固醇試劑（Roche Diagnostics Chol/HP 704036)溶離速度為 0·16 毫升 / 分鐘、經 由Τ-連結混合管柱流出物，而且混合物係通過沒入37°C水 85504.doc -129- 200406371 浴之15 m x 0.5 mm内徑之編織管線反應器。因膽固醇存在 所生產之有S產物係利用505 nm之偵測流速，而且偵測器 ， 之同源電流係轉化成數位信號以供收集與分析。將相當於 ' 膽固醇濃度變化之電流改變相對於時間畫圖，並利用Perkin · Elmer Turbochrome軟體計算相當於極低密度脂蛋白（VLDV) 、低密度脂蛋白（LDL)與高密度脂蛋白（HDL)溶離之曲線下 之面積。 將接受本發明化合物劑量之小鼠的血清三甘油脂量與接 了φ 受載體之小力者比較，以辨識特別可用以降低三甘油脂之 7^ 化合物。通常'與對照組比較，經過30毫克/公斤劑量後若 三甘油脂降低大於或等於30% (三十百分比）即意謂該化合 物別可用以降低三甘油脂含量。Sterols and triglycerides. This method was modified from published research (cf. McGowan M. W. et al., Clin Chem 29: 538-542, 1983; Allain C. C. et al. Clin Chem 20: 470-475, 1974). Commercially available standard triglycerides and total cholesterol, commercially available control plasma and samples were measured in duplicate using 200 microliters of reagent. Add another aliquot to 200 μl of water to provide a blank control for each sample. The culture plate was incubated in the culture plate with shaking gas: Lt temperature, and total cholesterol and triglyceride were measured at 500 nm and 540 nm, respectively. The values of the positive control group all fell within a predetermined range, and the coefficients of sample variation were all below 10%. All samples from each experiment are analyzed simultaneously to minimize variation between analyses. Serum lipoproteins were isolated and cholesterol was quantified by fast protein liquid chromatography (FPLC) coupled to a host-controlled detection system. Cholesterol reagent (Roche Diagnostics Chol / HP 704036) dissolves at a rate of 0.16 ml / min through the T-linked mixing column effluent, and the mixture is passed through 37 ° C water 85504.doc -129- 200406371 bath 15 mx 0.5 mm inner diameter braided line reactor. The S product produced by the presence of cholesterol uses a detection flow rate of 505 nm, and the homologous current of the detector is converted into a digital signal for collection and analysis. Plot the change in current equivalent to the change in cholesterol concentration versus time, and calculate the equivalent of very low density lipoprotein (VLDV), low density lipoprotein (LDL), and high density lipoprotein (HDL) using Perkin · Elmer Turbochrome software. The area under the curve. The amount of triglyceride in the serum of the mice receiving the dose of the compound of the present invention was compared with that of the mice receiving the φ acceptor to identify compounds that are particularly useful for reducing triglyceride. Generally 'compared with the control group, if the triglyceride is reduced by 30% (thirty percent) after a dose of 30 mg / kg, it means that the compound can be used to reduce the triglyceride content.

將接受本發明化合物之小鼠的血清HDLc量增加之百分 比與接受載體之小鼠者比較，以辨識特別可用以升高HDL 量之化合物。通常，經過30毫克/公斤劑量後，若HDLc量增 加大於或等# 25% (二十五百分比）即意謂該化合物別可用 以升高HDLc含量。 若能選出既可降低膽固醇含量又可增加HDLc含量之本 發明化合物，可以說是特別令人期待。然而，若僅可降低 膽固醇含量或是可增加HDLc含量之本發明化合物，還是很 有用。 db/db小鼠之血糖含量許估 進行對施用5種不同之本發明化合物之不同劑量與已知 之PPAR γ激動劑或PPAR α激動劑與對照組對於雄性db/db 85504.doc -130- 200406371 小鼠之血糖之效果研究。 τ 5週大&lt; 雄性糖尿病小藏（例如，c57B胸細协_二The percentage increase in the amount of HDLc in the serum of mice receiving the compound of the present invention is compared with that of mice receiving the vehicle to identify compounds that are particularly useful for increasing the amount of HDL. Generally, after a dose of 30 mg / kg, if the HDLc amount is increased by more than or equal to # 25% (twenty-five percent), it means that the compound can not be used to increase HDLc content. It can be said that it is particularly desirable to select compounds of the present invention that can reduce both the cholesterol content and the HDLc content. However, it is still useful if the compounds of the present invention can only reduce cholesterol content or increase HDLc content. The blood glucose content of db / db mice was estimated. Different doses of 5 different compounds of the invention were administered with known PPAR gamma agonists or PPAR alpha agonists and control groups. For male db / db 85504.doc -130- 200406371 Effect of Blood Sugar in Mice. τ 5 weeks old &lt; Male Diabetes (for example, c57B Chest Fine Association_ 二

(db〕，jacks0n Laborat〇ry，細η_〇γ，_或無脂肪之同窩仔广 於每個籠中各放6隻，而且隨時可取得食物與飲水。在2週 (通應期後’藉耳朵之刻痕辨識個別之小R，秤重並經由 尾巴靜脈放血以決定起始之血糖含量。由未禁食之_收 集血液⑽微升），其做法是藉由將每隻老鼠包覆於毛巾， 以解』刀切除尾巴並將採自尾巴之血擠入含肝素之毛細管 中。將樣本’&gt;王入裝置膠分離器之含肝素之微量容器，並】 保存於冰上。離心後取得血漿，即刻測定血糖。當進~ 行所有樣本之血糖與三甘油脂分析時，將剩餘之血衆:凍 ’直至實驗完成。將動物根據起始血糖量與體重分組。隔 天早上開始，每天經口給小鼠灌食共7天劑量。接受之處理 為又測化合物（30¾克/公斤）、正對照組藥劑（3〇毫克/公斤） 或載體[1%羧甲基纖維素（重量/體積）/含〇25%吐溫8〇 (重量 /體積），0·3|升/小鼠]。在第7天，於給予劑量後3小時，將 小队秤重並採血（尾巴靜脈）。在第7次劑量後24小時（亦即第 8天），再次對動物採血（尾巴靜脈）。將於第〇、7與8天，自-清醒之動物取得之樣本進行血糖分析。採血後24小時，將 動物秤重並給予最終劑量。於給予劑量之第8天後3小時， 令動物吸入異氟甲氧氟烷而麻醉之，並經心臟穿刺取得血 液（0·5〜0.7毫升）。將全血轉移至血清分離管，於冰上冷卻 並令其凝固。血清係於4°C離心後取得，並冷凍至進行化合 物量分析時。採頸椎脫臼法殺死小鼠後，將其肝、心與副 J 85504.doc -131 - 200406371 睪之脂肪塊切出並秤重。(db), jacks0n Laboratry, fine η_〇γ, _ or fat-free littermates are placed in 6 cages per cage, and food and water are available at any time. Within 2 weeks (after the onset 'Identify the individual small R by the score of the ear, weigh and bleed blood through the tail vein to determine the initial blood glucose level. Collect the blood from the unfasted _ microliters), by wrapping each mouse Cover the towel with a knife to cut off the tail and squeeze the blood collected from the tail into the capillaries containing heparin. Store the sample '&gt; Micro-container containing heparin in the gel separator of the device and keep it on ice. The plasma was obtained after centrifugation, and the blood glucose was measured immediately. When the blood glucose and triglyceride analysis of all samples was performed, the remaining blood was frozen: until the experiment was completed. The animals were grouped according to the initial blood glucose and weight. At the beginning, the mice were orally administered daily for a total of 7 days. The treatment received was a test compound (30¾ g / kg), a positive control agent (30 mg / kg), or a vehicle [1% carboxymethyl cellulose (Weight / volume) / with 25% Tween 80 (weight / volume), 0 · 3 | L / mouse]. On day 7, 3 hours after the dose was administered, the team was weighed and blood was collected (tail vein). 24 hours after the 7th dose (ie, day 8), again Blood is collected from the animals (tail vein). Blood glucose analysis will be performed on samples taken from-awake animals on days 0, 7, and 8. Twenty-four hours after blood collection, the animals are weighed and given the final dose. Three hours after the day, the animals were anesthetized by inhaling isoflurane, and blood was obtained by cardiac puncture (0.5 to 0.7 ml). The whole blood was transferred to a serum separation tube, cooled on ice and allowed to solidify Serum was obtained after centrifugation at 4 ° C, and frozen until the amount of compound was analyzed. After the mice were killed by cervical dislocation method, their liver, heart and accessory J 85504.doc -131-200406371 were cut into fat mass. Out and weigh.

利用色差法、藉市售之試劑測定血糖。根據製造商之說 明，該方法係將發表之研究做修正（參照，MaGowanM.W·， Artiss，J. D·，Strandbergh，D. R. &amp; Zak，Β· Clin Chem，20:470-5 (1974)與 Keston，A. Specific colorimetric enzymatic analytical reagents for glucose.第 129次Meeting ACS，31C(1956))，而 且對每莫耳分析物有賴釋出1莫耳過氧化氫，偶合於由 Trinder (Trinder, P. Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann Clin Biochem，6:24 (1969))首先提出之顏色反應。所產生之染料 的吸收與樣本中之分析物成線性相關。在本實驗室，我們 將該分析進一步修正供96槽型式之用。市售之血糖標準品 、市售之品質控制的血漿與樣本（2或5微升/槽）皆利用200微 升試劑進行二重複測定。將另一等份之樣本吸入第3槽並以 200微升水稀釋之，以提供每個樣本之空白對照。對於血糖 ，令培養培養盤震動氣上室溫下保溫18分鐘，並於培 養盤讀取器讀取其500 nm之吸收。將樣本之吸收與標準曲 線者（血糖為100-800)比較。品質控制樣本之值皆落於預定 範圍，而且樣本變異之係數皆在10%以下。同時分析每個實 驗之所有樣本，以將各分析間之變異降至最低。 研究結果意謂，本發明化合物可明顯降低db/db小鼠血糖 量；同時，所造成之體重增加亦比就已知標準所觀察者小。 本發明化合物對於Ay小鼠體重、脂肪質量、血糖與胰島素 量之效果之評估 85504.doc -132- 200406371 雌性am、氧 —令雌ΑΧ獨居、養於標準化條件（饥、各叫、時之曰 夜週期），並在研究期間自由取得食物與飲水。於2〇週大時 ，根據體重與藉DEXA掃描評估之體脂肪含量，令小鼠任意 分配至載體對照組與治療組（N=6)。然後，於日週期起Μ 小時後（例如，約午前7點）經口灌t給小鼠載體或本發明化 合物劑量（50毫克/公斤）共18天。在整個研究期，每天种體 重。於14第天時’將㈣養在個別之代謝室，以進行能量 消耗與能源到用之間接色差評估。於第18天時，再次令小 鼠進行DEXA掃描，以便測量治療後之身體組成份。 評估經口服施予化合物劑量18天後之體重、脂肪質量與 痩肉質量，並建議本發明之那種化合物尤其可用以維持所 需體重與/或促進所需之痩肉對脂肪之質量。 間接色差測定透露治療動物在夜週期時呼吸商數（RQ)之 明顯減少[G.864±G.()13 (對照組）相對於G8G3±;().⑻7 (治療 組）’ ρ&lt;0·0^1]。此RQ之明顯減少，係動物在其活動（夜）週 期時脂肪利％增加之指標。此夕卜，治療之動物&amp;對照組動 物展現明顯教高之能量消耗（分別為17·40 ± 0·49‘相對於 13.62±0.26仟卡/公斤/小時）。 雄性KK/Ay+氣 令雄KK/AM、鼠獨居、養於標準化條件（22艽、各12小時 之日夜週/、月），並在研死期間自由取得食物與飲水。於2 〇週 大時，根據血糖含量，令小鼠任意分配至載體對照組與治 療組。然後，於日週期起始丨小時後（午前7點）經口灌食給小 85504.doc -133- 200406371 鼠載體或本發明化合物劑量（30毫克/公斤）共14天。於第14 天時，評估盂糖、三甘油脂與胰島素量。 評估經口服施予化合物劑量14天後之血糖、三甘油脂與 胰島素，以辨識尤其適宜之本發明化合物。 化合物5 (8)之降低LDL-膽固醇總-膽固醇輿三甘油脂效果 之闡明方法 令重80-120克之雄性敘利亞蒼鼠（Harlan Sprague Dawley) 於利用前接受高脂肪、富含膽固醇之膳食達2至3週。在整 _ 個研究期間j由供應食物與飲水。在這些條件下，蒼鼠變成 士 高膽固醇血性，血漿膽固醇量介於180-280毫克/100毫升（餵 食正常食物之蒼鼠之總血漿膽固醇量介於100-150毫克/100 毫升）。根據總膽固醇量，利用市售程式，將具高血膽固醇 之蒼鼠（180毫克/100毫升及以上）任意分成治療組。Blood glucose was measured by color difference method using commercially available reagents. According to the manufacturer's instructions, the method was modified from published studies (Reference, MaGowan M.W., Artiss, J. D., Strandbergh, DR & Zak, Beta Clin Chem, 20: 470-5 (1974) With Keston, A. Specific colorimetric enzymatic analytical reagents for glucose. The 129th Meeting ACS, 31C (1956)), and it is dependent on the release of 1 mole of hydrogen peroxide per mole of analyte, coupled with Trinder (Trinder, P Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann Clin Biochem, 6:24 (1969)) was the first color reaction proposed. The absorption of the resulting dye is linearly related to the analyte in the sample. In this laboratory, we further refined this analysis for the 96-slot format. Commercially available blood glucose standards, commercially available quality-controlled plasma and samples (2 or 5 μl / well) were tested in duplicate using 200 μl reagent. Another aliquot was drawn into the third tank and diluted with 200 μl of water to provide a blank control for each sample. For blood glucose, incubate the culture plate with shaking gas at room temperature for 18 minutes, and read the 500 nm absorption on the culture plate reader. Compare the absorption of the sample to the standard curve (100-800 blood glucose). The values of the quality control samples all fall within a predetermined range, and the coefficients of sample variation are all below 10%. All samples from each experiment are analyzed simultaneously to minimize variation between analyses. The results of the study imply that the compounds of the present invention can significantly reduce blood glucose levels in db / db mice; meanwhile, the resulting weight gain is smaller than that observed by known standards. Evaluation of the effect of the compounds of the present invention on the body weight, fat mass, blood glucose and insulin amount of Ay mice 85504.doc -132- 200406371 Female am, oxygen-make female AX live alone and keep under standardized conditions Day-night cycle) and free access to food and water during the study period. At 20 weeks of age, mice were randomly assigned to the vehicle control group and the treatment group based on body weight and body fat content assessed by DEXA scans (N = 6). Then, the vehicle or the compound of the present invention (50 mg / kg) is orally administered to the mouse for a total of 18 days after M hours from the daily cycle (for example, about 7 o'clock noon). Body weight was daily throughout the study period. On the 14th day ', it will be maintained in a separate metabolism room for the assessment of the color difference between energy consumption and energy use. On day 18, mice were again subjected to a DEXA scan to measure body composition after treatment. The body weight, fat mass, and carcass mass after 18 days of the dose of the compound administered orally are evaluated, and it is suggested that the compound of the present invention is particularly useful for maintaining the required body weight and / or promoting the desired mass of carcass to fat. Indirect color difference measurement revealed that the respiratory quotient (RQ) of the treated animals was significantly reduced during the night cycle [G.864 ± G. () 13 (control group) vs. G8G3 ±; (). ⑻7 (treatment group) 'ρ &lt; 0 · 0 ^ 1]. This apparent decrease in RQ is an indicator of the percentage increase in fat gain of an animal during its active (night) period. Furthermore, the treated animals & control animals exhibited significantly higher energy expenditures (17.40 ± 0.49 ′ vs. 13.62 ± 0.26 kcal / kg / hr). Male KK / Ay + Qi Ling male KK / AM, rats lived alone, raised in standardized conditions (22 艽, 12 hours each day and night week / month), and free access to food and water during study death. At the age of 20 weeks, mice were randomly assigned to the vehicle control group and the treatment group according to the blood glucose content. Then, 85504.doc -133- 200406371 rat carrier or a dose of the compound of the present invention (30 mg / kg) was orally administered 14 hours after the start of the daily cycle (7 o'clock noon) for a total of 14 days. On day 14, assess the amount of glycosyl, triglycerides and insulin. Blood glucose, triglycerides, and insulin were evaluated 14 days after the dose of the compound administered orally to identify compounds of the invention that are particularly suitable. Compound 5 (8) clarifies the effect of reducing LDL-cholesterol total-cholesterol and triglyceride, allowing male Syrian guinea pigs (Harlan Sprague Dawley) weighing 80-120 g to receive a high-fat, cholesterol-rich diet before use for 2 To 3 weeks. Food and water were provided throughout the study period. Under these conditions, guinea pigs become hypercholesterolemic, with a plasma cholesterol level of 180-280 mg / 100 ml (the total plasma cholesterol of guinea pigs fed normal food is 100-150 mg / 100 ml). Based on total cholesterol, guinea pigs with high blood cholesterol (180 mg / 100 ml and above) were randomly divided into treatment groups using commercially available programs.

將本發明之一種化合物溶解於水性載體（包含具有吐溫 80之CMC)，使每隻蒼鼠每天藉灌食接受約1毫升、劑量為3 至30毫克/公斤體重之溶液。施予劑量為200毫克/公斤之非 諾貝特（Fenofibrate)(西格瑪化學公司，以相同載體製備懸浮 液）做為已知之α激動劑對照組，至於空白對照組則僅為載 體。施予劑量係在大清早，共14天。 血脂肪之定量： 於最後測試日，施予劑量2小時後，於令蒼鼠接受異氟甲氧氟 烷麻醉之同時，自其眶下竇採血（400微升）。將血液樣本收集 於冰浴冷卻之添加肝素之微離心管中。藉簡單離心將血漿 樣本與血球分離。總膽固醇與三甘油脂係遵照製造商之方 85504.doc -134- 200406371 法利用酶分析於 Monarch 設備（Instrumentation Laboratory) 自動進行加玖決定。血漿脂蛋白（VLDL、LDL與HDL)之解 構係藉注射25微升收集之血漿樣本於FPLC系統、經磷酸鹽 緩衝鹽液以0.5毫升/分鐘溶離過維持於室溫之6 HR 10/30管 柱。分離之血脂肪之偵測與定特徵係藉將流出物與膽固醇 /HP試劑（例如Roche Lab System，灌注率0· 12毫升/分鐘）後 管柱保溫於維持在37°C之編織之反應線圈。形成顏色之強 度與膽固醇濃度成正比、，且係利用分光光度計於505 nm測 定之。 一 本發明化合物施用14天之效果，係研究其相對於載體群 時LDL量之減少百分比。本發明之特佳化合物降低LDL之效 果，明顯地比非諾貝特強很多。與載體比較，可降低大於 或等於30% (三十百分比）LDL量之本發明化合物，尤其是吾 人所期待者。 亦進行本發明化合物之總膽固醇與三甘油脂降低效果之 研究。將經施用本發明化合物14天後總膽固醇與三甘油脂 降低之資料澳載體者比較，以建議特別為吾人所需要之化 合物。測量已知對照組之效果。 PPAR調節劑之纖維蛋白原降低效果之闡明方法 Zucker胖大鼠模式： 對本發明化合物之纖維蛋白原降低效果之研究的生命相 ，是該相同化合物之抗糖尿病研究之生命相方法之一部分 。在治療期最後一天（第14天），令動物處於手術麻醉下，藉 心臟穿刺收集〜3毫升之血於含檸檬酸緩衝液之注射筒。冷 85504.doc -135- 200406371A compound of the present invention is dissolved in an aqueous carrier (including CMC with Tween 80) so that each guinea pig receives a solution of about 1 ml and a dose of 3 to 30 mg / kg body weight by feeding. Fenofibrate (Sigma Chemical Co., Ltd., a suspension prepared with the same carrier) was administered at a dose of 200 mg / kg as a known alpha agonist control group, while the blank control group was only a carrier. The administered dose was early in the morning for 14 days. Blood fat quantification: On the last test day, 2 hours after the dose was administered, guinea pigs were anesthetized with isoflurane and blood was collected from the infraorbital sinus (400 μl). Blood samples were collected in ice bath-cooled heparin-added microcentrifuge tubes. The plasma sample is separated from the blood cells by simple centrifugation. Total cholesterol and triglycerides are determined by the manufacturer's method 85504.doc -134- 200406371 using enzyme analysis at the Monarch facility (Instrumentation Laboratory). The destructuring of plasma lipoproteins (VLDL, LDL, and HDL) was obtained by injecting 25 μl of collected plasma samples in the FPLC system and dissolving them in phosphate buffered saline at 0.5 ml / min. 6 HR 10/30 tubes maintained at room temperature column. The detection and characterization of the separated blood fat is made by effluent and cholesterol / HP reagent (such as Roche Lab System, perfusion rate 0 · 12ml / min), and the column is maintained at a braided reaction coil maintained at 37 ° C. . The intensity of color formation is directly proportional to the cholesterol concentration and is measured at 505 nm using a spectrophotometer. -The effect of the compounds of the present invention for 14 days was studied as a percentage reduction in the amount of LDL relative to the carrier population. The effect of the particularly good compound of the present invention in reducing LDL is significantly stronger than that of fenofibrate. Compared with the carrier, the compound of the present invention can reduce the amount of LDL greater than or equal to 30% (thirty percent), especially what we expect. Studies have also been conducted on the effects of reducing total cholesterol and triglycerides of the compounds of the present invention. Comparing those with reduced cholesterol and triglyceride data carriers after 14 days of administration of the compounds of the present invention to suggest compounds that are particularly desirable to us. The effect of the known control group was measured. Method for clarifying fibrinogen reduction effect of PPAR modulator Zucker fat rat model: The life phase of the study of the fibrinogen reduction effect of the compound of the present invention is part of the life phase method of the anti-diabetic study of the same compound. On the last day (day 14) of the treatment period, animals were placed under surgical anesthesia, and ~ 3 ml of blood was collected by cardiac puncture in a syringe containing citrate buffer. Cold 85504.doc -135- 200406371

卻血液樣本，並於4°C離心以分離於進行纖維蛋白原分析前 係貯存於-70X之血漿。 大鼠血漿纖維蛋白原之定量： 大鼠血漿纖維蛋白原之量，係利用市售含凝結機制之分 析系統，根據製造商之方法來決定。就實質言，自每個檢 體採樣100微升血漿，並利用緩衝液製備1/20稀釋液。將稀 釋之血漿保溫於37°C、經240秒。然後添加50微升之凝結試 劑-外用凝血酶溶液（由機制製造者提供之標準濃度）。該機 制可偵測參_:考標準樣本而定量之凝結時間-纖維蛋白原濃 度之函數。〜 結果： 本發明化合物也許可以在活體内降低纖維蛋白原含量。 比載體更能降低纖維蛋白原含量之化合物尤令人期待。 本發明化合物之降低膽固醇與三甘油脂效果也許可在 Zucker大鼠複製。 本發明化勿之抗體重增加與抗含慾效果之闡明方法 對Zucker胖i鼠或ZDF大鼠模式之14天研究： 令相當年齡與重量之非糖尿病雄性Zucker胖大鼠（CharlesBlood samples were centrifuged at 4 ° C to separate plasma stored at -70X prior to fibrinogen analysis. Quantification of rat plasma fibrinogen: The amount of rat plasma fibrinogen is determined using a commercially available analysis system containing a clotting mechanism, according to the manufacturer's method. In essence, 100 microliters of plasma was sampled from each specimen and a 1/20 dilution was prepared using buffer. The diluted plasma was incubated at 37 ° C for 240 seconds. Then 50 μl of coagulation reagent-topical thrombin solution (standard concentration provided by the mechanism manufacturer) was added. The mechanism can detect the coagulation time-the function of fibrinogen concentration quantified by reference standard samples. ~ Results: The compounds of the present invention may reduce fibrinogen content in vivo. Compounds that reduce fibrinogen content more than carriers are particularly desirable. The cholesterol-lowering and triglyceride-lowering effects of the compounds of the present invention may also be replicated in Zucker rats. The method for clarifying the effect of increasing the antibody weight and anti-desire effect of the present invention on a 14-day study of the model of Zucker fat rat or ZDF rat: To make non-diabetic male Zucker fat rats of comparable age and weight (Charles

River Laboratories，Wilmington，MA)或雄性ZDF大鼠(Genetic Models，Inc，Indianapolis，IN)於治療前先適應環境1週。在 整個時間，大鼠接受的是正常食物與無限制之飲水。 □-激動劑係溶解於水性載體，使每隻老鼠每天接受0.1、 0.3、1與3毫克/公斤劑量之約1毫升溶液之灌食。施予劑量 為300毫克/公斤之已知為α激動劑之非諾貝特（西格瑪化學 一 85504.doc -136- 200406371 公司，以相同載體製備懸浮液），並以載體為對照組。施予 劑量係在大清早，共14天。實驗期過後，偵測體重與實務 5 消耗。 利用此分析，可辨識尤其需要且可能造成明顯之體重減 -輕之本發明化合物。 本發明之某些特徵對醫藥用途可能特佳。下文將本發明 之具體實施例與本發明範疇内之化合物之特徵列成表格型 式，且其一或多種可獨立合併，以提供多種本發明之化合 ϋ 物與具體實施例。下列具體實施例之表格型式係做為本發 3 明之說明，而~且，無論如何皆非用以限制本發明之申請專 利範圍之範疇。 A)下式之化合物：River Laboratories, Wilmington, MA) or male ZDF rats (Genetic Models, Inc, Indianapolis, IN) were conditioned for 1 week before treatment. Throughout the time, rats received normal food and unlimited drinking water. □ -agonist is dissolved in an aqueous carrier, and each mouse receives about 1 ml of a solution of 0.1, 0.3, 1 and 3 mg / kg per day. A dose of 300 mg / kg of fenofibrate known as an alpha agonist (Sigma Chemical Co., Ltd. 85504.doc -136-200406371, a suspension was prepared with the same carrier) was used as a control group. The dose was administered early in the morning for 14 days. After the experimental period, measure body weight and practice 5 consumption. Using this analysis, compounds of the invention can be identified which are particularly needed and may cause significant weight loss. Certain features of the invention may be particularly good for medical use. In the following, the specific examples of the present invention and the characteristics of the compounds within the scope of the present invention are tabulated, and one or more of them can be independently combined to provide a variety of compounds and specific examples of the present invention. The table types of the following specific embodiments are described in the present invention, and are not intended to limit the scope of the patentable scope of the present invention in any way. A) a compound of the formula:

C)下式之化合物：C) a compound of the formula:

85504.doc -137- 20040637185504.doc -137- 200406371

〇 D)下式之化合物：〇 D) Compound of the formula:

E) R2係選自下列各基組成之群E) R2 is selected from the group consisting of

F) R2 為·CH(C(0)0CH3)苄基； G) R6係選自下列各基組成之群，氫、烷基與芳基 基’而其Ci-C^fe基與芳基-C〇_4-燒基係各自獨立經 85504.doc -138- 200406371 選自R5’之基所取代； H) R2為茫貌基，其中該芳基為苯基而該烷基為C2-C3烷 基，而該苯基係經由1至3個各自獨立之選自R2’之基所取代； I) R1為氫； J) ) R2為芳基（C2-C3)fe基，其為未經取代或經由1至3個各 自獨立之選自R2’之基所取代； K) R2為經C1-C2烷基取代之芳烷基； L) R5為Η或甲基。 Μ)下式之一匕合物：F) R2 is · CH (C (0) 0CH3) benzyl; G) R6 is selected from the group consisting of hydrogen, alkyl and aryl 'and its Ci-C ^ fe group and aryl- C〇_4-alkyl groups are each independently substituted with a group selected from 85504.doc -138- 200406371 selected from R5 '; H) R2 is a manganyl group, wherein the aryl group is phenyl and the alkyl group is C2-C3 An alkyl group, and the phenyl group is substituted by 1 to 3 groups independently selected from R2 ′; I) R1 is hydrogen; J)) R2 is an aryl (C2-C3) fe group, which is not Substituted or substituted by 1 to 3 groups independently selected from R2 '; K) R2 is aralkyl substituted with C1-C2 alkyl; L) R5 is fluorene or methyl. Μ) One of the following formulas:

N) 烷基； O) R6為甲基； P) E為 C(R3)(R4)A ; Q) R5為1或甲基； R) R3為Cr_C3烷氧基； S) E為 C(R3)(R4)A，而 A為 C(0)0R26，R26為 Η或 Ci-C3烷 基； T) 一種選自下列各物組成之群之化合物： (2S，l’R)_2-乙氧基-3-(4-{1’·[2-(4·苯氧基-苯基）-乙基胺甲 醯基]-乙氧基卜苯基）-丙酸，（2S，l’R)-2-乙氧基 -3-(4-{l’-[2- (4 -乙基-苯基）-乙基胺甲醒基]-乙氧基}-苯 基）_丙酸，（2S，l’R)-2-乙氧基_3-(4-{1’-[2-(4-三氟甲基 -139- 85504.doc 200406371 苯基）-乙基胺甲醯基]-乙氧基}-苯基）_丙酸； (2S，氧基_3-(4-{1’-[2-(2-乙氧基-苯基）_乙基胺甲 ^ 醯基]-乙氧基}•苯基）-丙酸； ^ (2S，l’R)-2_乙氧基-3-{4-[1’·(3-三氟甲基-芊基胺甲醯基）_ - 乙氧基]-苯基}-丙酸； (2S，l’R)_2-乙氧基_3-{4-[1’_(3-氟基_5·三氟甲基-芊基胺甲 醯基）-乙氧基]-苯基卜丙酸； (28，1’幻-3_(4-{1’-[(二苯基-3-基甲基）-胺甲酸基]_乙氧基}_ 苯基氧基-丙酸； j —» 〜 (2S，l’R)-M4]l’-[2-(3-氯基-苯基）-乙基胺甲醯基]•乙氧基} -苯基）-2-乙氧基-丙酸； (2S，l’R)-2 -乙氧基-3-(4{1’-[2_(3_氟基-苯基)-乙基胺$醯基] -乙氧基}-苯基）-丙酸； (2S，l’R)-2-乙氧基-3·(4{1’-[2_(2-氟基-苯基)-乙基胺甲醯基] &quot;乙氧基}•苯基）-丙酸； (2S，1 'R)-3-(4 {1’·[2_(2,4-二氯基-苯基）-乙基胺甲酸基]-乙 _ _ 氧基}-苯~基）-2-乙氧基-丙酸； ' (2S，1’ΙΙ)-3_(4{Γ·[2-(2,6_二氯基-苯基）-乙基胺甲醯基]乙 氧基}-苯基）-2-乙氧基-丙酸； (2S，l’R)_3-(4{l’-[2-(2-氯基·苯基）_乙基胺甲醯基]乙氧基}· . 苯基）-2_ 乙氧基·丙酸，（2S，l’R)_3-(4{l，-[2_(4-第三丁基 -苯基）-乙基胺甲醯基]-乙氧基卜苯基）-2-乙氧基-丙酸； (2S，l’R)-2·乙氧基-3-{4-[Γ-(4-氟基-芊基胺甲醯基）_乙氧 基]-苯基}-丙酸，（2S，l’R)_2-乙氧基-3-{4-[1，-(4-三氟甲 一 85504.doc -140- 200406371 基-苄基胺甲醯基）-乙氧基]-苯基卜丙酸； (2S，rR)-3-t4-[l，-(4-第三-丁基-爷基胺甲醯基）_乙氧基]·苯 ， 基}-2_ 乙氧基-丙酸，（2S，l，R)-3-{4-[l，-(4-第三丁基-苯’ 基胺甲醯基）-乙氧基]_苯基卜2-乙氧基-丙酸’（2S，l’R)&quot; -3-{4-[1，-(4-反式-第三-丁基_環己基胺甲醯基）_乙氧基] -苯基}-2-乙氧基-丙酸； (2S)-3-{4-[l-(4-第三-丁基-環己基胺甲醯基）-1_甲基-乙氧 基]-苯基}-2-甲氧基」丙酸； 1 (2S&gt;-2-甲氧#-3-(4-{1-甲基-1-[2-(4-苯氧基-苯基）-乙基胺 :3 甲醯基]-乙~氧基}-苯基丙酸； (2S)-3-(4-{l-[2-(2-乙氧基·苯基）-乙基胺甲醯基]-1-甲基-乙 氧基卜苯基]-2-甲氧基-丙酸； 2-甲氧基-3-(4-{l-甲基-1-[2-(3•三氟甲基-苯基）-乙基胺甲醯 基]-乙氧基卜苯基）_丙酸； (2S)-2-甲氧基-3-{4-[l-甲基-1-(3-三氟甲基-苄基胺甲醯基）_ 乙氧基]-苯基}&quot;&quot;丙酸’（2S)-3_(4-{l-[2_(2-氯基-苯基）_乙 ·參 基胺曱驢基])-1-甲基-乙氧基卜苯基）-2-甲氧基-丙酸； -==¾. (2S)-3-(4-{l-[(二苯基-3-基甲基)-胺甲醯基]-1·甲基·乙氧基卜 苯基）-2-甲氧基-丙酸； (2S)-3-(4-{l-[2-(2,5-二甲氧基-苯基）-乙基胺甲醯基]_；[ •甲 . 基-乙氧基}-苯基]-2-甲氧基·丙酸； (2S)-3-(4-{l_[2-(2·氟基-苯基）-乙基胺甲醯基]-1-甲基-乙氧 基}-苯基）-2-甲氧基-丙酸； (2S)-2-乙氧基-3·(4-{1-甲基-l-[2-(3-三氟甲基-苯基）_乙基 - 85504.doc -141 - 200406371 胺甲醯基]-乙氧基卜苯基）-丙酸； (2S)-2-乙氧基-3-{4-[l-(3-氟基-5-三氟甲基-苄基胺甲醯基）二 -1-甲基-乙氧基]-苯基卜丙酸； ， (2S)-3-(4-{l-[2-(2-氯基-苯基）-乙基胺甲醯基]-1-甲基-乙氧 -基}-苯基）-2 -乙氧基-丙’（2S)-3-(4-{l_[(二苯基_3_基甲 基）-胺甲酸基]-1-甲基-乙乳基}&quot;豕基）-2 -乙氧基-丙酸； (2S)_3-(4-{l-[2-(3·氯基-苯基）-乙基胺甲醯基]-1-甲基-乙氧 基}-苯基）-2-乙氧基^丙酸； Λ (2S&gt;-3-(4-{l^[2-(2,5-二甲氧基-苯基）_乙基胺甲醯基卜卜甲 3 基-乙氧基f -苯基）-2 -乙氧基-丙fee， (28)_2_乙氧基_3-(4-{1-[2-(2-氟基-苯基）-乙基胺甲酸基]-1-甲基-乙氧基}-苯基）-丙酸； (2S)-3-{3-[l-(4•第三-丁基-壤己基胺甲酿基）_1_甲基-乙氧 基]-苯基}-2 -甲氧基-丙酸， (2S)-3-{3-[l-(3-氟基-5-三氟甲基-苄基胺甲醯基）_1_甲基-乙 氧基]-苯基}-2 -甲氧基-丙酸； 二_ (2S)-3-(3-{l-[(二苯基-3_基甲基）-胺甲驢基]-1_甲基-乙氧基} _ - 苯基）-2-甲氧基-丙酸； ^ (2S)_3-(3-{l-[2-(3-氯基-苯基）_乙基胺甲醯基&gt;1-甲基-乙氧 基}-苯基）-2 -甲氧基-丙酸； (2S)-2-甲氧基-3-{4-[(l-苯基-乙基胺甲醯基）·甲氧基]-苯基} -丙酸； (2S)_3-(3-{l-[2-(2,4-二氯基-苯基）_乙基胺甲酸基]-1-甲基_ 乙氧基卜苯基）-2-甲氧基-丙酸； - 85504.doc -142- 200406371 (23)_3_(3-{卜[2-(2,6-二氯基_苯基）-乙基胺甲醯基]-1-甲基- 乙氧基}#基）-2_甲氧基-丙酸； 1 (2S)-3_(4-{l-[2-(2,4-二氯基-苯基）_乙基胺甲醯基l·1·甲基-^ 乙氧基}-苯基-甲氧基-丙故， (2S)-3-(4_{l-[2-(2,4-二氯基-苯基）-乙基胺甲醯基]_卜甲基- 乙氧基卜苯基）-2-乙氧基-丙酸； (2S)-3-(4-{l-[2-(2,6-二氯基-笨基）-乙基胺甲醯基]-1_甲基_N) alkyl; O) R6 is methyl; P) E is C (R3) (R4) A; Q) R5 is 1 or methyl; R) R3 is Cr_C3 alkoxy; S) E is C (R3 ) (R4) A, and A is C (0) OR26, R26 is fluorene or Ci-C3 alkyl; T) a compound selected from the group consisting of: (2S, l'R) _2-ethoxy 3- (4- {1 '· [2- (4 · phenoxy-phenyl) -ethylaminomethyl] -ethoxyphenyl) -propionic acid, (2S, l'R ) -2-ethoxy-3- (4- {l '-[2- (4-ethyl-phenyl) -ethylaminomethylmethyl] -ethoxy} -phenyl) -propionic acid, (2S, l'R) -2-ethoxy_3- (4- {1 '-[2- (4-trifluoromethyl-139- 85504.doc 200406371 phenyl) -ethylaminomethylmethyl ] -Ethoxy} -phenyl) _propionic acid; (2S, oxy_3- (4- {1 '-[2- (2-ethoxy-phenyl) _ethylaminomethyl) fluorenyl ] -Ethoxy} • phenyl) -propionic acid; ^ (2S, l'R) -2_ethoxy-3- {4- [1 '· (3-trifluoromethyl-fluorenylaminomethyl) Fluorenyl) _- ethoxy] -phenyl} -propionic acid; (2S, l'R) _2-ethoxy_3- {4- [1 '_ (3-fluoroyl_5 · trifluoromethyl) -Aminomethylamidino) -ethoxy] -phenylpropanoic acid; (28,1'-Magic-3_ (4- {1 '-[(diphenyl-3-ylmethyl) -amine Formate] _B } _Phenyloxy-propionic acid; j — »~ (2S, l'R) -M4] l '-[2- (3-chloro-phenyl) -ethylaminemethyl]] ethyl Oxy} -phenyl) -2-ethoxy-propionic acid; (2S, l'R) -2 -ethoxy-3- (4 {1 '-[2_ (3-fluoro-phenyl) -Ethylamine $ fluorenyl] -ethoxy} -phenyl) -propionic acid; (2S, l'R) -2-ethoxy-3 · (4 {1 '-[2_ (2-fluoro group -Phenyl) -ethylaminomethyl] &quot; ethoxy} • phenyl) -propionic acid; (2S, 1 'R) -3- (4 {1' · [2_ (2,4-di (Chloro-phenyl) -ethylcarbamate] -ethyl_oxy} -phenyl ~ yl) -2-ethoxy-propionic acid; '(2S, 1'ΙΙ) -3_ (4 {Γ · [2- (2,6-dichloro-phenyl) -ethylaminomethyl] ethoxy} -phenyl) -2-ethoxy-propionic acid; (2S, l'R) _3- (4 {l '-[2- (2-chloro-phenyl) _ethylaminomethylmethyl] ethoxy}.. Phenyl) -2_ethoxy · propionic acid, (2S, l'R ) _3- (4 {l,-[2_ (4-Third-butyl-phenyl) -ethylaminomethyl] -ethoxyb-phenyl) -2-ethoxy-propionic acid; (2S , L'R) -2 · ethoxy-3- {4- [Γ- (4-fluoro-fluorenylaminomethylamidino) _ethoxy] -phenyl} -propionic acid, (2S, l 'R) _2-ethoxy-3- {4- [1,-(4-trifluoromethane-8 5504.doc -140- 200406371yl-benzylaminomethyl) -ethoxy] -phenylpropanoic acid; (2S, rR) -3-t4- [l,-(4-third-butyl -Methylaminomethyl) -ethoxy] · benzene, yl} -2_ethoxy-propionic acid, (2S, l, R) -3- {4- [l,-(4-tert-butyl -Phenyl 'phenylaminomethylmethyl) -ethoxy] -phenylphenyl 2-ethoxy-propionic acid' (2S, l'R) &quot; -3- {4- [1,-(4- Trans-third-butyl-cyclohexylaminemethylamidino) _ethoxy] -phenyl} -2-ethoxy-propionic acid; (2S) -3- {4- [l- (4- Tert-butyl-cyclohexylaminemethylmethyl) -1-methyl-ethoxy] -phenyl} -2-methoxy "propanoic acid; 1 (2S &gt; -2-methoxy # -3- (4- {1-methyl-1- [2- (4-phenoxy-phenyl) -ethylamine: 3 methylamidino] -ethyl ~ oxy} -phenylpropionic acid; (2S)- 3- (4- {l- [2- (2-ethoxy · phenyl) -ethylaminomethylmethyl] -1-methyl-ethoxybenzenephenyl] -2-methoxy-propyl Acid; 2-methoxy-3- (4- {l-methyl-1- [2- (3 • trifluoromethyl-phenyl) -ethylaminomethylmethyl] -ethoxyphenyl ) _Propionic acid; (2S) -2-methoxy-3- {4- [l-methyl-1- (3-trifluoromethyl-benzylamine formamyl) _ethoxy] -benzene Radical} &quot; &quot; propionic acid '(2S) -3_ (4- {l- [2_ ( (2-Chloro-phenyl) _ethenylamine and ammonyl])-1-methyl-ethoxyp-phenyl) -2-methoxy-propionic acid;-== ¾. (2S)- 3- (4- {l-[(diphenyl-3-ylmethyl) -aminomethylmethyl] -1 · methyl · ethoxyphenylphenyl) -2-methoxy-propionic acid; ( 2S) -3- (4- {l- [2- (2,5-dimethoxy-phenyl) -ethylaminomethyl}]; [• methyl.ethoxy-ethoxy} -phenyl ] -2-methoxy · propionic acid; (2S) -3- (4- {l_ [2- (2 · fluoro-phenyl) -ethylaminomethylmethyl] -1-methyl-ethoxy } -Phenyl) -2-methoxy-propionic acid; (2S) -2-ethoxy-3 · (4- {1-methyl-1- [2- (3-trifluoromethyl- Phenyl) _ethyl- 85504.doc -141-200406371 Carboxamido] -ethoxybuphenyl) -propionic acid; (2S) -2-ethoxy-3- {4- [l- ( 3-Fluoro-5-trifluoromethyl-benzylaminemethylamidino) di-1-methyl-ethoxy] -phenylpropanoic acid; (2S) -3- (4- {l- [2- (2-Chloro-phenyl) -ethylaminomethylmethyl] -1-methyl-ethoxy-yl} -phenyl) -2 -ethoxy-propyl '(2S) -3- (4- {l _ [(diphenyl_3_ylmethyl) -carbamate] -1-methyl-ethyllactyl} &quot; fluorenyl) -2 -ethoxy-propionic acid; (2S) _3- (4- {l- [2- (3 · Chloro-phenyl) -ethylaminomethylmethyl] -1-methyl -Ethoxy} -phenyl) -2-ethoxy ^ propanoic acid; Λ (2S &gt; -3- (4- {l ^ [2- (2,5-dimethoxy-phenyl) _ethyl Methylamine formamidine, methyl 3-yl-ethoxy f-phenyl) -2 -ethoxy-propyl fee, (28) _2_ethoxy_3- (4- {1- [2- ( 2-fluoro-phenyl) -ethylcarbamate] -1-methyl-ethoxy} -phenyl) -propionic acid; (2S) -3- {3- [l- (4 • third -Butyl-phosphinohexylamine methyl) 1-methyl-ethoxy] -phenyl} -2 -methoxy-propionic acid, (2S) -3- {3- [l- (3-fluoro Methyl-5-trifluoromethyl-benzylaminomethane) 1-methyl-ethoxy] -phenyl} -2-methoxy-propionic acid; di_ (2S) -3- (3- {l-[(diphenyl-3-ylmethyl) -aminomethyldonyl] -1_methyl-ethoxy} _ -phenyl) -2-methoxy-propionic acid; ^ (2S) _3- (3- {l- [2- (3-Chloro-phenyl) _ethylaminomethyl} &gt; 1-methyl-ethoxy} -phenyl) -2 -methoxy-propyl Acid; (2S) -2-methoxy-3- {4-[(l-phenyl-ethylaminomethylmethyl) · methoxy] -phenyl} -propionic acid; (2S) _3- ( 3- {l- [2- (2,4-dichloro-phenyl) _ethyl carbamate] -1-methyl_ethoxybphenyl) -2-methoxy-propionic acid; -85504.doc -142- 200406371 (23) _3_ (3- {Bu [2- (2,6-dichloroyl_phenyl ) -Ethylaminomethylmethyl] -1-methyl-ethoxy} #yl) -2-methoxy-propionic acid; 1 (2S) -3_ (4- {l- [2- (2, 4-dichloro-phenyl) -ethylaminomethylmethyl 1.1-methyl- ^ ethoxy} -phenyl-methoxy-propyl, (2S) -3- (4_ {l- [2- (2,4-dichloro-phenyl) -ethylaminomethyl] -methyl-ethoxyphenyl) -2-ethoxy-propionic acid; (2S) -3- ( 4- {l- [2- (2,6-dichloro-benzyl) -ethylaminomethylmethyl] -1_methyl_

乙氧基}-苯基）_2_乙氧基-丙酸； (2S)_2-乙氧基-3-(4-{1·[2-(4-乙基·苯基）-乙基胺甲醯基]-1_ 甲基-乙氧基}-苯基）-丙酸； (2S)-2-乙氧基-3-(4-{1·[2_(2-乙氧基-苯基）-乙基胺甲醯基] -I-甲基-乙氧基}-苯基）-丙酸； 2-乙氧基-3-{ 4-[1-(3-三氟甲基-爷基胺甲醯基）-乙氧基]-苯 基卜丙酸； 2 -乙氧基-3-{4-[1-(5 -氟基-3·三氟甲基-爷基胺甲醯基）·乙氧 基l·苯基卜丙酸； 2-乙氧基-3-{4-[l-(3-苯基-苄基胺甲醯基）_乙氧基卜苯基卜 丙酸；- 2-乙氧基-3 _ {4-[1-(4-苯氧基-苯基乙基胺甲醯基）_乙氧基]_ 苯基}-丙酸； 2- 乙氧基-3 · {4-[1-(3-三氟甲基-苯基乙基胺甲醯基）_乙氧基] -苯基}-丙酸； 3- (4-{1-[2-(2,6- 一鼠基-苯基）-乙基胺甲酸基]-乙氧基卜苯基) -2-乙氧基-丙酸； 85504.doc -143· 200406371 2-乙氧基-3-(4-{l-[2-(4-乙基-苯基）-乙基胺甲醯基]-乙氧基} -苯基）-， 2- 乙氧基- 3-(4-{l-[2-(4-乙基·冬基）-乙基胺T酸基]-乙氧基} -苯基）-丙酸； 3- (4-{環己基-[2_(4-乙基-苯基）-乙基胺甲醯基]-甲氧基}•苯 基）-2 -乙氧基-丙酸， 2-乙氧基-3-(4-{l-[2-(4-乙基-苯基）-乙基胺甲醯基]-2-苯基-Ethoxy} -phenyl) _2_ethoxy-propionic acid; (2S) _2-ethoxy-3- (4- {1 · [2- (4-ethyl · phenyl) -ethylamine Formamyl] -1_methyl-ethoxy} -phenyl) -propionic acid; (2S) -2-ethoxy-3- (4- {1 · [2_ (2-ethoxy-phenyl) ) -Ethylaminomethylmethyl] -I-methyl-ethoxy} -phenyl) -propionic acid; 2-ethoxy-3- {4- [1- (3-trifluoromethyl-y Methylaminomethyl) -ethoxy] -phenylpropanoic acid; 2-ethoxy-3- {4- [1- (5-fluoro-3-3 trifluoromethyl-famidamine) ) · Ethoxy l · phenylpropanoic acid; 2-ethoxy-3- {4- [l- (3-phenyl-benzylamine formamyl) _ethoxyphenylphenylpropane Acid;-2-ethoxy-3 _ {4- [1- (4-phenoxy-phenylethylaminemethylmethyl) _ethoxy] _phenyl} -propionic acid; 2-ethoxy -3-{4- [1- (3-trifluoromethyl-phenylethylaminemethylamidino) _ethoxy] -phenyl} -propionic acid; 3- (4- {1- [2 -(2,6-monomuryl-phenyl) -ethylcarbamate] -ethoxyphenylphenyl) -2-ethoxy-propionic acid; 85504.doc -143 · 200406371 2-ethoxy -3- (4- {l- [2- (4-ethyl-phenyl) -ethylaminomethylmethyl] -ethoxy} -phenyl)-, 2-ethoxy-3- (4 -{l- [2- (4-ethyl · winteryl)- Amine T acid group] -ethoxy} -phenyl) -propionic acid; 3- (4- {cyclohexyl- [2_ (4-ethyl-phenyl) -ethylaminomethylmethyl] -methoxy } • phenyl) -2-ethoxy-propionic acid, 2-ethoxy-3- (4- {l- [2- (4-ethyl-phenyl) -ethylaminomethylmethyl] -2-phenyl-

乙氧基}-苯基）-丙酸、與 (2S，1 氧基_3-{4-[l’_(2-p塞吩-2-基·乙基胺甲醯基）_ 乙氧基]-苯~基卜丙酸；及 其醫藥可接受之鹽； U)—種選自下列各物組成之群之化合物： (2S，1 R)-3-{4-[l’-(4-第三-丁基-環己基胺甲醯基）-乙氧基]_ 冬基}_2·乙氧基-丙酸； (2S，l’R)_2-乙氧基-3-(4{Γ_[(嘧吩-2-基甲基）_胺甲醯基]•乙 氧基} _苯基)-丙酸； (2S，l’R)-2_乙氧基-3-{4-[1，-(2-嘧吩-2_基-乙基胺甲醯基）_ 乙氧基]-苯基}-丙酸，及 其醫藥可接受之鹽； V)—種選自下列各物組成之群之化合物： (2S，l’R)-2_乙氧基庚基胺甲醯基-乙氧基）_苯基]_ 丙酸； (2S)-3-[3-(l_庚基胺甲醯基β1_甲基-乙氧基）_苯基]-2-甲氧基 -丙酸； 一 85504.doc -144- 200406371 (2S)-2-乙氧基-3-[4-(l-庚基胺甲醯基-1-T基-乙氧基）-苯基] -丙酸，乙氧基-3·(4-{1-[2-(4-乙基-苯基）-乙基胺甲醯 基]-丙氧基}_苯基）_丙酸； 2-乙氧基-3·(4-{1-[2-(4-苯氧基-苯基）·乙基胺甲醯基]-丙氧 基} •苯基）-丙酸’及 其醫藥可接受之鹽； W) —種選自下列各物組成之群之化合物： (2S)-3-(4_{2-[4-(4•氟基τ爷酿基）-旅淀_1·基]_2_氧基-乙氧基} -苯基）-2-甲氧基-丙酸； (2S)_3_(4_ {2:[+-(4_氯基爷醯基）略淀_1_基]_2_氧基-乙氧基} -苯基）-2-甲氧基-丙酸； (2S)-3-[4-(2-{4-[雙-(4-氟基·苯基）-甲基]-哌畊-1-基卜2-氧 基-乙氧基）-苯基]-2-甲氧基-丙酸； (2S)-3-(4-{2_[4-(2-氟基-苯基）-哌畊-1·基]-2-氧基-乙氧基卜 苯基）-2-甲氧基-丙酸； (2 S)-3 - [4-(2-{4-[(4-氯基-苯基）_苯基-甲基]•喊p井基卜2· 氧基-乙^基）-苯基]-2-甲氧基-丙酸； (2S)_3-(4-{2_[4-(4-乙酸基苯基）·旅畊小基]_2_氧基·乙氧基} -苯基）-2-甲氧基-丙酸； (28)-3-[4_(2_{4-[(4-氯基-苯基）-苯基-甲基]-喊_-1_基卜2-氧基-乙氧基）-苯基]-2-甲氧基-丙酸； (2S)-3-{4-[2-(4·二苯甲基-哌畊-1-基）-2-氧基·乙氧基]-苯基} -2-甲氧基-丙酸； (2S)_3-(4-{2-[4-(4·氟基·爷基）-哌畊-1-基]·2·氧基乙氧基卜 苯基）-2-甲氧基-丙酸； 85504.doc -145- 200406371 (2S)-3-{4-[2-(3,4-二氫-1H-異喹啉-2-基）-2-氧基-乙氧基]-苯 基}_2_甲寬基-丙酸；Ethoxy} -phenyl) -propionic acid, and (2S, 1oxy_3- {4- [l '_ (2-p phenphen-2-yl · ethylaminomethylmethyl) _ ethoxy Phenyl] -benzene ~ phenylpropionic acid; and pharmaceutically acceptable salts thereof; U)-a compound selected from the group consisting of: (2S, 1 R) -3- {4- [l '-( 4-Third-butyl-cyclohexylaminemethylamidino) -ethoxy] _dongyl} _2 · ethoxy-propionic acid; (2S, l'R) _2-ethoxy-3- (4 {Γ _ [(pyrimin-2-ylmethyl) _carbamoyl] • ethoxy} _phenyl) -propionic acid; (2S, l'R) -2_ethoxy-3- {4 -[1,-(2-pyrimyl-2_yl-ethylaminomethylmethyl) _ethoxy] -phenyl} -propionic acid, and pharmaceutically acceptable salts thereof; V)-a species selected from the following Compounds of each group: (2S, l'R) -2_ethoxyheptylamine formamyl-ethoxy) _phenyl] _propionic acid; (2S) -3- [3- ( l_heptylaminemethylamido β1_methyl-ethoxy) _phenyl] -2-methoxy-propionic acid; 85504.doc -144- 200406371 (2S) -2-ethoxy-3 -[4- (l-heptylaminomethylamido-1-Tyl-ethoxy) -phenyl] -propionic acid, ethoxy-3 · (4- {1- [2- (4-ethyl -Phenyl) -ethylaminomethyl] -propoxy} _phenyl) _propionic acid; 2-ethoxy-3 · ( 4- {1- [2- (4-phenoxy-phenyl) · ethylaminomethyl] -propoxy} • phenyl) -propionic acid 'and its pharmaceutically acceptable salts; W) — A compound selected from the group consisting of the following: (2S) -3- (4_ {2- [4- (4 • fluoro group τ 酿 brewing group)-Ludian_1 · yl] _2_oxy-B Oxy} -phenyl) -2-methoxy-propionic acid; (2S) _3_ (4_ {2: [+-(4_chloromethylamidyl) slightly _1_yl] _2_oxy- Ethoxy} -phenyl) -2-methoxy-propionic acid; (2S) -3- [4- (2- {4- [bis- (4-fluoro · phenyl) -methyl]- Pipen-1-ylb 2-oxy-ethoxy) -phenyl] -2-methoxy-propionic acid; (2S) -3- (4- {2_ [4- (2-fluoroyl- Phenyl) -piperazine-1.yl] -2-oxy-ethoxyp-phenyl) -2-methoxy-propionic acid; (2 S) -3-[4- (2- {4- [(4-Chloro-phenyl) _phenyl-methyl] • Hydroxy-2-ethyl-oxy] -phenyl] -2-methoxy-propionic acid; (2S) _3 -(4- {2_ [4- (4-acetoxyphenyl) · Travelling small group] _2_oxy · ethoxy} -phenyl) -2-methoxy-propionic acid; (28)- 3- [4_ (2_ {4-[(4-Chloro-phenyl) -phenyl-methyl] -sho_-1_ylb 2-oxy-ethoxy) -phenyl] -2- Methoxy-propionic acid; (2S) -3- {4- [2- (4-benzyl-piperazine-1-yl -2-oxy · ethoxy] -phenyl} -2-methoxy-propionic acid; (2S) _3- (4- {2- [4- (4 · fluoroyl · methylidene) -pipeline -1-yl] · 2 · ethoxyethoxyphenylphenyl) -2-methoxy-propionic acid; 85504.doc -145- 200406371 (2S) -3- {4- [2- (3,4 -Dihydro-1H-isoquinolin-2-yl) -2-oxy-ethoxy] -phenyl} _2_m-widenyl-propionic acid;

對掌體 (2S)_3-(4_{2-[4-(4-氟基·苯基）-哌畊_1_基]·2_氧基-乙氧基卜 冬基）-2-甲氧基-丙酸； (2S&gt;-2-甲氧〜棊冬4][2_(2_甲氧基-苯基乙基胺甲醯基卜甲 氧基卜笨基&gt;丙酸； (23)-3-(4-{2-[4-(3-氯基-苯基）-喊畊_1_基]_2_氧基-乙氧基}-苯基）·2-甲氧基-丙酸； (2S)_3-(4_{2-[4-(4_氯基-苄基）-哌畊_1-基]_2_氧基_乙氧基卜 苯基）-2-甲氧基-丙酸，（2S)-2_甲氧基·3_{4_[2_氧基-2_(4-對-甲苯基-哌畊_1_基）-乙氧基]-苯基卜丙酸； (2S)-2·甲氧|-3-(4_{2-氧基-2-[4-(4_三氟甲基_苯基哌畊 -1-基]-乙氧基卜苯基）_丙酸；及 其醫藥可接受之鹽。 X) 一種選自下列各物組成之群之化合物： (2S)-3-(‘{[芊基-(丨-苯基-乙基）-胺甲醯基]-甲氧基}-笨基） -2_甲氧基·丙酸；(2S) _3- (4_ {2- [4- (4- (fluorofluorophenyl) -piperin_1-yl] · 2-oxy-ethoxybudongyl) -2-methoxy -Propionic acid; (2S &gt; -2-methoxy ~ hydrazone 4] [2_ (2-methoxy-phenylethylaminemethylamidomethylmethoxybenzyl)> propionic acid; (23)- 3- (4- {2- [4- (3-Chloro-phenyl) -houtyl_1_yl] _2_oxy-ethoxy} -phenyl) · 2-methoxy-propionic acid ; (2S) _3- (4_ {2- [4- (4_Chloro-benzyl) -piperin_1-yl] _2_oxy_ethoxyphenylphenyl) -2-methoxy- Propionic acid, (2S) -2_methoxy · 3_ {4_ [2_oxy-2_ (4-p-tolyl-piperin_1_yl) -ethoxy] -phenylpropanoic acid; (2S) -2 · methoxy | -3- (4_ {2-oxy-2- [4- (4-trifluoromethyl_phenylpiperin-1-yl] -ethoxyphenyl) _Propionic acid; and pharmaceutically acceptable salts thereof. X) A compound selected from the group consisting of: (2S) -3-('{[fluorenyl- (丨 -phenyl-ethyl) -amine Methylamino] -methoxy} -benzyl) -2-methoxy · propionic acid;

CH, 對掌體 85504.doc -146- 200406371 (2S)-3-(4-{[乙基-(2-氟基-苄基）-胺甲醯基]_甲氧基}_苯基） -2-甲氧基二丙酸； 1 (2S)-3-[4-({乙基-[2-(4-甲氧基·苯基）小甲基·乙基]_胺甲醯 ’ 基}-甲氧基）-苯基]_2·甲氧基-丙酸； ， (2S)-3-(4-{[乙基-(3-甲基-苄基）-胺甲醯基]_甲氧基苯基） -2-甲氧基-丙酸；CH, p-body 85504.doc -146- 200406371 (2S) -3- (4-{[ethyl- (2-fluoro-benzyl) -carbamoyl] _methoxy} _phenyl) 2-methoxydipropionic acid; 1 (2S) -3- [4-({ethyl- [2- (4-methoxy · phenyl) small methyl · ethyl] _amine formamidine ' } -Methoxy) -phenyl] _2 · methoxy-propionic acid;, (2S) -3- (4-{[ethyl- (3-methyl-benzyl) -aminomethane] _Methoxyphenyl) -2-methoxy-propionic acid;

(2S)-2-甲氧基-3-{4-[(甲基-蕃-1_基甲基-胺甲驗基）_甲氧基] -苯基}-丙酸； (2S)_3-(4-{[^r基-(1-苯基-乙基）-胺甲醯基]•甲氧基卜苯基） •2-甲氧/基二丙酸； (2S)-3-(4-{[ 丁基-(1-苯基-乙基）-胺甲醯基 &gt; 甲氧基卜苯基） -2-甲氧基-丙酸； (2S)-2-甲氧基-3-(4-{[甲基-(1-苯基-乙基 &gt;胺甲醯基]_甲氧 基}-苯基）-丙酸； (2S)-3-(4-{[苄基-(2•乙氧羰基-乙基）_胺甲醯基]-甲氧基卜苯 基）-2 -甲氧基_丙酸；及 其醫藥可接受之鹽。 (2S)_3-(4-{[苄基-(2-乙氧羰基·乙基胺甲醯基]_甲氧基卜苯 基）-2-甲氧基-丙酸； (2S)-3-{4-[(苄基-苯乙基-胺甲醯基）_甲氧基苯基卜2_甲氧 基_丙酸； (2S)-2-甲氧基-3-{4·[(1-甲氧羰基苯基·乙基胺甲醯基）_ 甲氧基]-苯基}-丙酸； (2S)-3-(4-{[苄基-(2-乙氧羰基_乙基胺甲醯基]_甲氧基卜苯- 85504.doc -147- 200406371 基）-2-甲氧基-丙酸； (2S)-3-(4-{[苯-并[1，3]-二氧戊環基甲基）_胺甲醯基]•甲氧^ 基}-苯基）-2-甲氧基-丙酸； ' (23)-3-{4-[(6-氟基-苯并嘍唑_2_基胺甲醯基）-甲氧基]-苯基} · -2-甲氧基-丙酸； (2S)-2-甲氧基-3-{4-[(l-萘-1_基_乙基胺甲醯基）-甲氧基]-苯 基卜丙酸； (2S)-2-甲氧基-3-(4-{[(莕-1-基甲基）_胺甲醯基]-甲氧基卜苯 _ 基）-丙酸一； -» — (28)-3-(4-(12-(^6-二氯基·苄毓基）_乙基胺甲醯基]-甲氧基} -苯基）-2·甲氧基-丙酸； (2S)-3-[4-({[(4_氯基-苯基）-苯基-甲基；I-胺甲醯基}_甲氧基） -苯基]-2 -甲氧基-丙酸； (2S)-3-{4-[(3,3-二苯基-丙基胺甲醯基）_甲氧基]-苯基卜2-甲 氧基）-丙酸； 2-甲氧基-2二y基-3-(4-{[2·(4-苯氧基-苯基）-乙基胺甲醯基]-甲氧基卜苯基）-丙酸； (2S)-2-甲氧基-3-(4-{[3-(甲基-苯基-胺基）_丙基胺甲醯基]-甲氧基}_苯基）-丙酸； (2S)-2-甲氧基-3-(4-{[3-(甲基-苯基-胺基）-丙基胺甲醯基]-· 甲氧基卜苯基）-丙酸； - (2S)-2-甲氧基-3-{4-[(l-甲氧羰基-2-苯基-乙基胺甲醯基）- 甲氧基]-苯基卜丙酸； &lt; (2S)-2-甲氧基·3-{4-[(2-吡啶-2·基-乙基胺甲醯基）-甲氧基]- 85504.doc -148- 苯基卜丙酸； (2S)-E-3-{4-ff4·第三-丁基-環己基胺甲醯基）-甲氧基]-苯基} -2-甲氧基）-丙酸； (2S)-Z-3-{4-[(4-第三-丁基-環己基胺甲醯基）-甲氧基]-苯基} -2 -甲氧基）-丙， (2S)-3-(4-環丁基胺甲醯甲氧基-苯基）-2-甲氧基-丙酸； (2S)-2-甲氧基-3-{4-[(1-甲基-3-苯基-丙基胺甲醯基）_甲氧 基]-苯基}-丙酸；、 (2S)-3-{4-[(S-第三-丁基-[1，3,4]嘧二唑-2_基胺甲醯基）_甲氧 基]-苯基}_2_甲氧基-丙酸； (2S)-3-{4-[(5-第三-丁基-[1，3,4]嘧二唑-2-基胺甲醯基）_甲氧 基]-苯基卜2-甲氧基-丙酸； (2S)-3-{4-[(4-第三·丁基-嘧唑-2-基胺甲醯基)_甲氧基]-苯基} -2-甲氧基-丙酸； 3-{4-[(5-環丙基-[1，3,4]嘧二唑-2_基胺甲醯基）_甲氧基]_苯 基}-2-甲氧基-丙酸； (2S)-2-甲氧i-3-(4-{[2-(4-苯氧基·苯基）-乙基胺甲醯基]-甲 氧i基} &quot;冬基）-丙敗， (2S)-3-{4_[(l，3-二甲基-丁基胺甲醯基）-甲氧基]-苯基卜2-甲 氧基-丙酸； (2S)-2-甲氧基- 3-{4-[(l -甲基-己基胺甲醯基）-甲氧基]-苯基} -丙酸； (2S)-2-甲氧基-3-{4-[(l-甲基-丁基胺甲醯基)-甲氧基]-苯基}· 丙酸； 85504.doc -149· 200406371 (2S)-2-甲氧基-3-{4-[(3-甲基-丁基胺甲醯基）-甲氧基]-苯基} -丙 fee， (2S)-3-{4-[(2,2,3,3,4,4,4-七氟基-丁基胺甲醯基)-甲氧基卜 苯基}-2-甲氧基-丙酸； (2S)-3-(4-環戊基胺甲醯甲氧基）-苯基）-2-甲氧基-丙酸； 3-{4-[(4-順式-第三-丁基-環己基胺甲醯基）-甲氧基]-苯基} -2-甲氧基-丙酸；及 其醫藥可接受之鹽；' Z) —種化_合物(2S) -2-methoxy-3- {4-[(methyl-fan-1_ylmethyl-aminomethanine) _methoxy] -phenyl} -propionic acid; (2S) _3 -(4-{[^ r group- (1-phenyl-ethyl) -aminomethylamino] • methoxybuphenyl) • 2-methoxy / yldipropionic acid; (2S) -3- (4-{[Butyl- (1-phenyl-ethyl) -aminomethylamino &gt; methoxymethoxyphenyl) -2-methoxy-propionic acid; (2S) -2-methoxy -3- (4-{[methyl- (1-phenyl-ethyl &gt; aminomethylamidino] _methoxy} -phenyl) -propionic acid; (2S) -3- (4-{[ Benzyl- (2 • ethoxycarbonyl-ethyl) _aminomethylmethyl] -methoxyphenylphenyl) -2-methoxy_propionic acid; and its pharmaceutically acceptable salts. (2S) _3- (4-{[benzyl- (2-ethoxycarbonyl · ethylaminemethylamidino] _methoxyphenyl) -2-methoxy-propionic acid; (2S) -3- {4- [ (Benzyl-phenethyl-aminemethyl) -methoxyphenyl group 2-methoxy-propionic acid; (2S) -2-methoxy-3- {4 · [(1-methoxy Carbonylphenyl · ethylaminemethylamidino) _methoxy] -phenyl} -propionic acid; (2S) -3- (4-{[benzyl- (2-ethoxycarbonyl_ethylaminemethylformamidine) Yl] -methoxyphenylbenzene-85504.doc -147- 200406371 yl) -2-methoxy-propionic acid; (2S) -3- (4-{[benzene-acyl [1,3] -dioxy Pentylmethyl) _Aminomethyl}] methoxymethoxy} -phenyl) -2-methoxy-propionic acid; '(23) -3- {4-[(6-Fluoro-benzoxazol_2_ Methylaminomethylmethyl) -methoxy] -phenyl} · -2-methoxy-propionic acid; (2S) -2-methoxy-3- {4-[(l-naphthalene-1_yl _Ethylaminemethylamidino) -methoxy] -phenylpropanoic acid; (2S) -2-methoxy-3- (4-{[(fluoren-1-ylmethyl) _aminoformamidine -] Methoxymethoxybenzyl) -propionic acid mono;-»— (28) -3- (4- (12-(^ 6-dichloro-benzyl) _ethylaminomethylmethyl ] -Methoxy} -phenyl) -2 · methoxy-propionic acid; (2S) -3- [4-({[(4-chloro-phenyl) -phenyl-methyl; I- Aminemethyl} -methoxy) -phenyl] -2 -methoxy-propionic acid; (2S) -3- {4-[(3,3-diphenyl-propylaminomethyl) _Methoxy] -phenylb 2-methoxy) -propionic acid; 2-methoxy-2diylyl-3- (4-{[2 · (4-phenoxy-phenyl)- Ethylaminomethylmethyl] -methoxybuphenyl) -propionic acid; (2S) -2-methoxy-3- (4-{[3- (methyl-phenyl-amino) _propane Methylaminomethylmethyl] -methoxy} -phenyl) -propionic acid; (2S) -2-methoxy-3- (4-{[3- (methyl-phenyl-amino) -propyl Methylaminomethylmethyl]-· methoxymethoxyphenyl) -propionic acid;-(2S) -2-methoxy -3- {4-[(l-methoxycarbonyl-2-phenyl-ethylaminemethylamidino) -methoxy] -phenylpropanoic acid; &lt; (2S) -2-methoxy · 3- {4-[(2-pyridin-2 · yl-ethylaminomethyl) -methoxy]-85504.doc -148-phenylpropionic acid; (2S) -E-3- {4 -ff4 · Third-butyl-cyclohexylaminemethylmethyl) -methoxy] -phenyl} -2-methoxy) -propionic acid; (2S) -Z-3- {4-[(4 -Third-butyl-cyclohexylaminemethylamidino) -methoxy] -phenyl} -2-methoxy) -propyl, (2S) -3- (4-cyclobutylaminemethylamidomethoxy) -Phenyl) -2-methoxy-propionic acid; (2S) -2-methoxy-3- {4-[(1-methyl-3-phenyl-propylaminomethyl)} Methoxy] -phenyl} -propanoic acid; (2S) -3- {4-[(S-third-butyl- [1,3,4] pyrimidazol-2-ylaminomethylmethyl) ) _Methoxy] -phenyl} _2_methoxy-propionic acid; (2S) -3- {4-[(5-third-butyl- [1,3,4] pyrimidazole-2 -Amineaminomethyl) -methoxy] -phenylb 2-methoxy-propionic acid; (2S) -3- {4-[(4-tert-butyl-pyrazol-2-yl Aminomethyl) -methoxy] -phenyl} -2-methoxy-propionic acid; 3- {4-[(5-cyclopropyl- [1,3,4] pyrimidazole-2_ Methylaminomethyl))-methoxy] -phenyl} -2-methoxy-propionic acid; (2S) -2-methoxyi- 3- (4-{[2- (4-phenoxy · phenyl) -ethylaminomethylmethyl] -methoxyiyl} &quot; dongyl) -propanil, (2S) -3- {4_ [(l, 3-dimethyl-butylaminomethylamidino) -methoxy] -phenylb 2-methoxy-propionic acid; (2S) -2-methoxy- 3- {4- [(l-methyl-hexylaminemethylamidino) -methoxy] -phenyl} -propionic acid; (2S) -2-methoxy-3- {4-[(l-methyl-butyl Aminomethyl) -methoxy] -phenyl} · propionic acid; 85504.doc -149 · 200406371 (2S) -2-methoxy-3- {4-[(3-methyl-butylamine (Methylfluorenyl) -methoxy] -phenyl} -propyl fee, (2S) -3- {4-[(2,2,3,3,4,4,4-heptafluoro-butylaminomethyl) (Methenyl) -methoxyphenylphenyl} -2-methoxy-propionic acid; (2S) -3- (4-cyclopentylamine formamidinemethoxy) -phenyl) -2-methoxy -Propionic acid; 3- {4-[(4-cis-third-butyl-cyclohexylaminemethylamidino) -methoxy] -phenyl} -2-methoxy-propionic acid; and Pharmaceutically acceptable salt; 'Z) — a chemical compound

，及其醫藥可接受之鹽； AA)—種半哌畊鹽化合物； BB) R5為甲基而R6為氫； CC) Rl^H ； DD) R2為芳烷基，其中該芳烷基為未經取代或經由1至3 個各自獨立之選自R2’之基組成之群所取代； EE) R2為芳烷基； FF) R2為方说基，而該芳基為苯基； GG)E為C(R3)(R4)A，而R3為氫且R4為烷氧基； HH) R4為乙氧基； II) A為 COOH ; JJ)以4為_基、Ci-Csfe基、C1-C5燒氧基、C3-C6%^燒基、 -150- 85504.doc 200406371 芳基CG-C4烷基、Cn烷氧芳基與苯基，其中該&lt;：1-05烷基、 CVC5烷氧基：^C3-C6環烷基、芳基CG-C4烷基、Ci-4烷氧芳基二 與苯基係各自獨立之未經取代或各自獨立之經由1至3個各 I 自獨立之選自R4’之基組成之群所取代，或R3與R4合併以形 . 成〇3-06環烷基； KK) R4係選自下列之基組成之群，CVC5烷氧基、C3-C6 環烷基、芳基C0_C4烷基、Cm烷氧芳基與苯基，其中該^/; 烷氧基、C3_C6環烷基 '芳基CG_C4烷基、Cm烷氧芳基與苯 基係各自之未經取代或各自獨立之經由1至3個各自獨立之 • —- ^ 選自R4’之基铒成之群所取代，或R3與R4合併以形成C3-C6 — 環烷基； LL) R2為芳基C2烷基； MM)芳基為苯基； NN)本發明化合物係調配成錠劑或膠囊； 00)本發明化合物係用以治療糖尿病； PP)本發明化合物係用以治療X症候群；And its pharmaceutically acceptable salts; AA) —a semipiperium salt compound; BB) R5 is methyl and R6 is hydrogen; CC) R1 ^ H; DD) R2 is an aralkyl group, wherein the aralkyl group is Unsubstituted or substituted by 1 to 3 groups each independently selected from R2 '; EE) R2 is aralkyl; FF) R2 is parsyl, and the aryl is phenyl; GG) E is C (R3) (R4) A, and R3 is hydrogen and R4 is alkoxy; HH) R4 is ethoxy; II) A is COOH; JJ) 4 is _ group, Ci-Csfe group, C1 -C5 alkyloxy, C3-C6% alkyl, -150- 85504.doc 200406371 aryl CG-C4 alkyl, Cn alkoxyaryl and phenyl, where the &lt;: 1-05 alkyl, CVC5 Alkoxy: ^ C3-C6 cycloalkyl, aryl CG-C4 alkyl, Ci-4 alkoxyaryl di and phenyl are independently unsubstituted or independently through 1 to 3 each I Substituted by a group selected from the group consisting of R4 ′, or R3 and R4 are combined to form a cycloalkyl group of 03-06; KK) R4 is a group selected from the group consisting of CVC5 alkoxy, C3 -C6 cycloalkyl, aryl C0_C4 alkyl, Cm alkoxyaryl and phenyl, where the ^ /; alkoxy, C3_C6 cycloalkyl'aryl CG_C4 alkyl, C m alkoxyaryl and phenyl are each unsubstituted or independently substituted by 1 to 3 independent groups — — ^ selected from the group consisting of R4 ′, or R3 and R4 are combined to form C3-C6 —cycloalkyl; LL) R2 is arylC2 alkyl; MM) aryl is phenyl; NN) The compound of the present invention is formulated into a tablet or capsule; 00) The compound of the present invention is used to treat diabetes; PP) The compounds of the present invention are used to treat syndrome X;

QQ)本發卞化合物係用以治療高量之血脂； RR)本發明之化合物係醫藥可接受之鹽； 在一本發明較佳化合物中： SS) R2為經取代之芳烷基而R1為氫； TT) R2為芳烷基、R1為氫、R5為氫、E為C(R3)(R4)A '而 A為COOR14，該芳烷基為未經取代或經由1至3個各自獨立 之選自R2’之取代基組成之群所取代； UU) R2為芳烷基、R1為氫、R5為氫、E為C(R3)(R4)A、 R4為C1-C3烷氧基、而A為COOR14，該芳烷基為未經取代 85504.doc -151- 200406371 或經由1至3個各自獨立之選自R2,之取代基組成之群所取 代； 二― VV) R2為芳基Ci-C3燒基、R1為氫、R5為氫、E為 C(R3)(R4)A、R4為C1-C3烷氧基、而A為COOR14，該芳烷 基為未經取代或經由1至3個各自獨立之選自R2，之取代基 組成之群所取代；QQ) This compound is used to treat high amounts of blood lipids; RR) The compound of the present invention is a pharmaceutically acceptable salt; In a preferred compound of the present invention: SS) R2 is a substituted aralkyl group and R1 is Hydrogen; TT) R2 is aralkyl, R1 is hydrogen, R5 is hydrogen, E is C (R3) (R4) A 'and A is COOR14, the aralkyl group is unsubstituted or independently through 1 to 3 Selected from the group consisting of substituents R2 '; UU) R2 is an aralkyl group, R1 is hydrogen, R5 is hydrogen, E is C (R3) (R4) A, R4 is C1-C3 alkoxy, And A is COOR14, and the aralkyl group is unsubstituted 85504.doc -151- 200406371 or substituted by 1 to 3 groups each independently selected from R2; di-VV) R2 is aryl Ci-C3 alkyl, R1 is hydrogen, R5 is hydrogen, E is C (R3) (R4) A, R4 is C1-C3 alkoxy, and A is COOR14, the aralkyl is unsubstituted or via 1 Up to 3 groups each independently selected from the group consisting of R2;

WW) R2為經取代之芳SCrG烷基、其中該取代係由1-2 個各自獨立之選自下列k基組成之群，CrCs烷基、鹵基與 Ci-Cs烷氧％^ R1為氫、R5為氫、E為 C(R3)(R4)A、R4為 Ci-C3 烷氧基、而AACOOR14 ; XX) R2為經取代之芳基CVC3烷基、其中該取代係由1-2 個各自獨立之選自下列之基組成之群所取代，Ci-Cs烷基與 CVC3烷氧基，R1為氫、R5為氫、E為 C(R3)(R4)A、R4為 CVC3 烷氧基、而A為COOR14 ; YY)R1係選自下列之基組成之群，氫、C1-C4烷基 '與芳WW) R2 is a substituted aryl SCrG alkyl group, wherein the substitution is a group consisting of 1-2 independently selected from the following k groups, CrCs alkyl, halo and Ci-Cs alkoxy% ^ R1 is hydrogen , R5 is hydrogen, E is C (R3) (R4) A, R4 is Ci-C3 alkoxy group, and AACOOR14; XX) R2 is a substituted aryl CVC3 alkyl group, wherein the substitution is 1-2 Each independently substituted by a group consisting of Ci-Cs alkyl and CVC3 alkoxy, R1 is hydrogen, R5 is hydrogen, E is C (R3) (R4) A, R4 is CVC3 alkoxy And A is COOR14; YY) R1 is a group selected from the group consisting of hydrogen, C1-C4 alkyl 'and aromatic

基C0-C4烷產，R2為芳基C0-C4烷基、雜芳基C0-C4烷基； ZZ) R2為芳基C0-C4烷基、C1-C8烷基、雜芳基C0-C4烷基 、C3-C6環烷基、C0-C4烷基C(O)雜C1-C8烷基、芳基雜C1_C8 烷基，其中該芳基C0-C4烷基、C1-C8烷基、雜芳基C0-C4 烷基、C3-C6環烷基、C0-C4烷基C(O)雜C1-C8烷基、芳基雜 C1-C8烷基係各自獨立之未經取代或各自獨立之經由1至3 個各自獨立之選自下列之基組成之群所取代，苯基、鹵苯 基、苯氧基、鹵基、鹵基C1-C4烷基、C1-C4烷氧基與C3_C6 環烷基； 85504.doc -152- 200406371 AAA) R1與R2共同形成哌啶基、哌啡基或二氫異喹琳基 ，其中哌啶基、哌畊基或二氫異喳啉基係各自獨立之未經 取代或各自獨立之經1至3個各自獨立之選自下列之基組成 之群所取代，C1-C4燒基、苯基、鹵苯基、三氟甲苯基、甲 基苯基、甲氧苯基、乙醯苯基、苄基、自芊基、字醯基、 鹵爷疏基、二氟甲爷si基、甲苄§1基、甲氧芊酸基、乙酸 芊驢基、一苯基亞甲基 '(苯基）（_苯基）亞甲基與二函苯亞 甲基。 、 相等意義：： 儘管，我們已特足展現本發明並參考其較佳具體實施例 做說明；然而，對熟諳此藝者應了解，在不偏離附屬之申 請專利範圍涵蓋之本發明範疇内，可對型式與細節做不同 變化。 85504.doc -153-C0-C4 alkyl, R2 is aryl C0-C4 alkyl, heteroaryl C0-C4 alkyl; ZZ) R2 is aryl C0-C4 alkyl, C1-C8 alkyl, heteroaryl C0-C4 Alkyl, C3-C6 cycloalkyl, C0-C4 alkyl C (O) hetero C1-C8 alkyl, aryl hetero C1-C8 alkyl, wherein the aryl C0-C4 alkyl, C1-C8 alkyl, hetero Aryl C0-C4 alkyl, C3-C6 cycloalkyl, C0-C4 alkyl C (O) hetero C1-C8 alkyl, aryl hetero C1-C8 alkyl are each independently unsubstituted or independently Substituted by 1 to 3 groups each independently selected from the group consisting of phenyl, halophenyl, phenoxy, halo, halo C1-C4 alkyl, C1-C4 alkoxy and C3_C6 ring Alkyl; 85504.doc -152- 200406371 AAA) R1 and R2 together form piperidinyl, piperidinyl, or dihydroisoquinolinyl, wherein piperidinyl, piperidinyl, or dihydroisofluorinyl are each independent Unsubstituted or independently substituted by 1 to 3 groups each independently selected from the group consisting of C1-C4 alkyl, phenyl, halophenyl, trifluorotolyl, methylphenyl, Methoxyphenyl, acetophenyl, benzyl, autofluorenyl, fluorenyl, halomethyl, difluoromethyl si, methylbenzyl§ 1-based, methanoic acid, acetonyl, monophenylmethylene '(phenyl) (_ phenyl) methylene and bis (methylene) phenylene. Equivalent meanings: Although we have fully demonstrated the present invention and explained with reference to its preferred embodiments; however, those skilled in the art should understand that within the scope of the present invention covered by the scope of the attached patent application, Different types and details can be changed. 85504.doc -153-

Claims (1)

200406371 拾、申請專利範園：200406371 Patent Park: (a) R1係選自下列各墓組成之群：氫、CVC8烷基、C3_C6 環烷參、芳基-C〇_4-烷基、雜芳基-C()_4_烷基、胺基Cl_c4 燒基、亡3_C6環垸芳基-CV2-燒基、芳基雜Ci-Cs燒基、 -CHC(0)Ci-C4燒氧基、CG_4_燒基燒基與 -CH2-C(0)-R15-R16 ;而且，其 Ci-C8燒基、C3-Cjf:燒 基、方基-C〇-4_^0基、雜方基-C〇_4-fe基、胺基Ci_C4 烷基、C3_C6環烷芳基-CG_2_燒基、芳基雜匚广^烷基、 -CHCCCOCi-C^烷氧基、C〇-4·烷基-(^((^雜匕-仏烷基與 -CH^^(0)-R15-R16係各自獨立之未經取代或經由1 至3個各自獨立之選自R1’之取代基組成之群取代者 ;而且’其中之R15為Ο或NH，而R16為視情形之未 經取代或經由1至3個各自獨立之選自R16,之取代基 組成之群取代之芊基； (b) R1’與R2’係各自獨立之由下列之基組成之群·· 烷基、Ca-C6環烷基、C^-C：5烷氧基、芳*C(rC2烷氧基 、鹵基Ci-C3垸基、自基、芳基、燒基、-C(O)-芳基、鹵基Ci-C5燒氧基、芳基Ci-C5燒基與二芳基 - 85504.doc 200406371(a) R1 is selected from the group consisting of: hydrogen, CVC8 alkyl, C3_C6 naphthene, aryl-C0_4-alkyl, heteroaryl-C () _ 4-alkyl, amine Cl_c4 alkyl, 3-C6 cyclofluorenyl-CV2-alkyl, aryl hetero-Ci-Cs alkyl, -CHC (0) Ci-C4 alkyl, CG_4_alkyl, and -CH2-C (0 ) -R15-R16; Moreover, its Ci-C8 alkyl group, C3-Cjf: alkyl group, square group-C0-4_ ^ 0 group, hetero square group-C0_4-fe group, amino Ci_C4 alkyl group , C3_C6 cycloalkylaryl-CG_2_alkyl, arylheteroalkyl, alkyl, -CHCCCOCi-C ^ alkoxy, C0-4alkyl-(^ ((hetero-alkyl- and alkyl) -CH ^^ (0) -R15-R16 are each independently unsubstituted or substituted by a group consisting of 1 to 3 independent substituents selected from R1 '; and' wherein R15 is 0 or NH, R16 is unsubstituted or substituted by 1 to 3 independent groups selected from R16, as appropriate; (b) R1 'and R2' are each independently composed of the following groups Groups · alkyl, Ca-C6 cycloalkyl, C ^ -C: 5 alkoxy, aryl * C (rC2 alkoxy, halo Ci-C3 fluorenyl, self-based, aryl, alkyl, -C (O) -aryl, halo Ci-C5 , Aryl Ci-C5 group and burn diaryl - 85504.doc 200406371 C1-C5虎基；而且，其-C(O)-芳基係未經取代或經由1 至3個1^自獨立之選自下列取代基組成之群取代者 :鹵基、Ci-C5燒基、鹵基Ci-C5燒基、（^95燒氧基與 -c(o)cvc5烷基；而且，其芳*cvc5烷基、二芳基 C1 _C5燒基與芳基係各自獨立之未經取代或經由1至3 個各自獨立之選自下列取代基組成之群取代者·· _ 基、Ci-Cs燒基、芳基、鹵基CVC5燒基、三鹵基Ci-C3 烷基、CrCs烷氧墓與芳基CrCs烷基； (c) R2係多自下列取代基組成之群：Cl_c8烷基、c3_c6 環燒，基、芳基-CG·4燒基、雜芳基_cQ-4-燒基、雜 環燒芳基、雜C1-C6環燒芳基C1-C4燒基、胺基 烷基、C^C：6環燒芳基-(:^-燒基、芳基雜(^-(：8烷基、 燒基、_CH(C(0)0CH3)节基與 -CH2-C(0)-R15，，-R16”，·而且，其Cl-C8燒基、C3_C6 環烷基、芳基_C〇·4·烷基、雜Ci-Q環烷芳基、雜CVC6 環基C1-C4燒基、雜芳基-Cw燒基、胺基(^_ς：4 烷基、C3_C6環烷芳基-c0·2•烷基、芳基雜。^^烷基、 C〇-4-烷基-C(O)雜 CVC8 烷基與·0：Η2-(：(Ο)-Ι115，，-Ι116，， 係各自獨立之未經取代或經由1至3個各自獨立之選 自R2 ’之取代基組成之群取代者； (d) R15”為 Ο或 ΝΗ ; (e) R16為未經取代或經由丨至3個各自獨立之選自Ri6， 之取代基組成之群取代之爷基； (f) R1與R2—起可以形成雜環，該雜環係未經取代或經· 85504.doc -2- 200406371 由1至3個各自獨立之選自R1，之取代基組成之群取代 者；二- — (g) E係選自下列取代基組成之群：C(R3)(R4)A、 ^ (CH2)nCOOR13、芳基-C〇.4-燒基、硫基燒基、 硫芳基、芳基Ci-CU烷氧基、CVC4烷氧基Ci-CU烷基、 月；方基與胺基Ci_C4fe基；而且，其（CH2)nCOORl 3、 芳基-Cw燒基、硫基-CVCV烷基、硫芳基、〇1&lt;4烷 氧芳基、C「C4烷氧基Ci_C4烷基、胺芳基與胺基(314 烷基各自獨立之未經取代或經由1至3個各自獨立豆 之選自E ’之取代基組成之群取代者； (h) R7’與R7”係各自獨立之選自Ci-C4烷基與Ci-C4鹵烷 基組成之群； (i) η與m係各自獨立之選自〇、1、2與3組成之群； (j) A係選自下列的基組成之群：（CH2)mc〇0R14、CVC3 燒基腈、叛醯胺、績胺、醯基續胺與四峻，而且， 其續胺、醯基績胺與四峻係各自獨立之未經取代或二馨 經由1至3個各自獨立之選自A，之取代基組成之群取一 代者； (k) A’係由下列之基組成之群：Ci-CU烷基、鹵烷基 、雜芳基與芳基，而且，其中該雜芳基與芳基係各 . 自獨立之未經取代或經由1至3個各自獨立選自下列 * 之取代基組成之群取代者：鹵基、Ci-Cs烷基、Ci-Cs 鹵烷基、CVC5烷氧基與-CCC^CrCs烷基； _ ⑴R3係選自下列的基組成之群：Η、Ci-Cs烷基、C1-C5 一 85504.doc 缔基與氧基； (m) R4係蓬自下列的基組成之群：η、鹵基、燒基 、CVCVM*氧基、C3-C6環燒基、芳基CG_C4^基與Cj-4 烷氧芳基，而且，其(VC5燒基、cvc5燒氧基、C3-C6 環烷基、芳基Co-C4烷基與Ci_4烷氧芳基係各自獨立之 未經取代或各自獨立之經由1至4個各自獨立選自R4， 之取代基組成之群取代者，或R3與R4係合併形成 〇3-(：6環烷基；、 (n) R5與及6係各自獨立之選自下列之基組成之群··氫、 CVC8燒—基、芳基-C〇_4_燒基、雜芳基-C〇_4-燒基、c3-C6 環烷芳基_c〇-2-烷基、C3_c0環烷基_Cq 2-烷基與 -CH2_C(0)-R17-R18 ;而且，其Cl_C8烷基、芳基-C〇4-烷基、雜芳基-Cw烷基、C3-C6環烷芳基-C〇-2-烷基、 C3-C6環燒基·&lt;：〇_2_燒基與 _ch2-C(0)-R17-R18 係各自 獨立之未經取代或經由1至3個各自獨立之選自R5，之 取代_產組成之群取代者； (ο) E’、R4’、R5’與R13”係各自獨立之由下列之基組成 之群·· C1-C5燒基、C1-C5烷氧基、C1-C5鹵烷基、C1-C5 鹵烷氧基、硝基、氰基、CH0、羥基、Ci-C4烷酸、 苯基、芳氧基、S〇2R7’、SR7，，、芳基C〇_2燒氧基、C1-C6 烷羧醯胺基與C00H ; (p) R16’係由下列的基組成之群，鹵基、Cl_c8烷基、芳 基、鹵燒基、三鹵CVC3烷基、CVC5烷氧基與芳基cvc5 烷基； 4- 200406371C1-C5 tiger group; and, its -C (O) -aryl group is unsubstituted or substituted through 1 to 3 groups independently selected from the following substituents: halo, Ci-C5 Group, halo Ci-C5 alkyl group, (^ 95 alkyloxy group and -c (o) cvc5 alkyl group; Moreover, its aryl * cvc5 alkyl group, diaryl C1-C5 alkyl group and aryl group are each independently independent Substituted or substituted by 1 to 3 groups each independently selected from the group consisting of Ci group, Ci-Cs alkyl group, aryl group, halo CVC5 alkyl group, trihalo Ci-C3 alkyl group, CrCs alkoxy tombs and aryl CrCs alkyl groups; (c) R2 is a group consisting of the following substituents: Cl_c8 alkyl, c3_c6 ring, group, aryl-CG · 4, and heteroaryl_cQ- 4-alkyl group, heterocyclic alkyl group, hetero C1-C6 cycloalkyl group C1-C4 alkyl group, aminoalkyl group, C ^ C: 6 cycloalkyl group-(: ^-alkyl group, aryl group (^-(: 8 alkyl group, alkyl group, _CH (C (0) 0CH3) benzyl group, and -CH2-C (0) -R15, -R16 ", and its Cl-C8 alkyl group, C3-C6 ring Alkyl, aryl_C0.4 alkyl, hetero Ci-Q cycloalkaryl, hetero CVC6 cyclo C1-C4 alkyl, heteroaryl-Cw alkyl, amine (^ _ς: 4 alkyl , C3_C6 cycloalkaryl-c0 · 2 • Alkyl, aryl hetero. ^ Alkyl, C0-4-alkyl-C (O) hetero CVC8 alkyl and · 0: Η 2- (: (0)-1115,--1116 ,, are independent of each other Unsubstituted or substituted by 1 to 3 groups consisting of independent substituents selected from R2 '; (d) R15 "is 0 or NΗ; (e) R16 is unsubstituted or through 3 to 3 Each independently selected from the group consisting of Ri6, a substituted group consisting of a substituent; (f) R1 and R2 together can form a heterocyclic ring, the heterocyclic ring is unsubstituted or via · 85504.doc -2- 200406371 by 1 To three independent groups of substituents selected from R1, each of which is substituted by (2) (g) E is selected from the group consisting of the following substituents: C (R3) (R4) A, ^ (CH2) nCOOR13 , Aryl-C0.4-alkyl, thioalkyl, thioaryl, aryl Ci-CU alkoxy, CVC4 alkoxy Ci-CU alkyl, sulphur; square and amine Ci_C4fe groups; Moreover, its (CH2) nCOORl 3, aryl-Cw alkyl group, thio-CVCV alkyl group, thioaryl group, 〇1 &lt; 4 alkoxyaryl group, C, C4 alkoxy Ci_C4 alkyl group, amine aryl group Amino (314 alkyl) each independently unsubstituted or selected from E through 1 to 3 independent beans (H) R7 'and R7 "are each independently selected from the group consisting of Ci-C4 alkyl and Ci-C4 haloalkyl; (i) η and m are each independently selected A group consisting of 0, 1, 2 and 3; (j) A is a group selected from the group consisting of: (CH2) mc00R14, CVC3 sulfenyl nitrile, benzylamine, pyridine, fluorenylamine and Sijun, and, its continuous amine, fluorenyl amine and Sijun are independently unsubstituted or dixin through one to three independent substituents selected from A, one generation; (k ) A 'is a group consisting of Ci-CU alkyl, haloalkyl, heteroaryl, and aryl, and wherein the heteroaryl and aryl are each independent or unsubstituted or via 1 to 3 substituents each independently selected from the group consisting of the following *: halo, Ci-Cs alkyl, Ci-Cs haloalkyl, CVC5 alkoxy and -CCC ^ CrCs alkyl; ⑴ ⑴R3 series A group selected from the group consisting of: fluorene, Ci-Cs alkyl, C1-C5 85504.doc alkenyl and oxy; (m) R4 is a group composed of the following groups: η, halo, Radical, CVCVM * oxy, C3-C6 cycloalkyl, CG_C4 ^ group and Cj-4 alkoxyaryl group, and (VC5 alkyl group, cvc5 alkyloxy group, C3-C6 cycloalkyl group, aryl Co-C4 alkyl group and Ci_4 alkoxyaryl group are each independent Unsubstituted or independently substituted through a group consisting of 1 to 4 substituents each independently selected from R4, or R3 and R4 are combined to form 03-(: 6 cycloalkyl ;, (n) R5 and And 6 are each independently a group selected from the group consisting of: hydrogen, CVC8-alkyl, aryl-C0_4-alkyl, heteroaryl-C0_4-alkyl, c3-C6 ring Alkylaryl_c0-2-alkyl, C3_c0 cycloalkyl_Cq 2-alkyl, and -CH2_C (0) -R17-R18; and Cl_C8 alkyl, aryl-C04-alkyl, Heteroaryl-Cw alkyl, C3-C6 cycloalkaryl-C0-2-alkyl, C3-C6 cycloalkyl, &lt;: 〇_2_alkyl and _ch2-C (0) -R17 -R18 is each independently unsubstituted or substituted by 1 to 3 independent groups selected from R5, and (产) E ', R4', R5 'and R13 "are each independently A group consisting of C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, C1-C5 haloalkoxy, nitro, cyano, CH0, hydroxyl, Ci-C4 alkyl Acid, phenyl, aryloxy, S02R7 ', SR7 ,, aryl C0_2 alkoxy, C1-C6 alkylcarboxyamido and C00H; (p) R16' is composed of the following groups Group, halo, Cl_c8 alkyl, aryl, halo, trihalo CVC3 alkyl, CVC5 alkoxy and aryl cvc5 alkyl; 4- 200406371 環纪基-C〇_2-燒基； 、 (r) R13與R14係各自獨jl選自下列之基組成之群：氫、 C1-C4烷基、芳基與芳甲基，而且其^―以烷基係各 自獨义之未經取代或各自獨立之經由1至3個各自獨 立之選自R13’之取代基組成之群取代者，而且其芳 甲基與芳基係各自獨互之未經取代或各自獨立之經 由1至厂3個各自獨立之選自R14,之取代基組成之群取1 代者; (s) R13’係由下列之基組成之群：C「C5烷基、c3_C6環烷 基、CVC5鹵烷基、（VC5烷氧基、芳氧基、鹵基、芳 基、_C(0)CVC5烷基、_C(0)·芳基、自基Ci-C5烷氧基 、芳基CVC5烷基與CrCs烷二芳基，而且，其-C(〇)_ 芳基、芳基、芳基C^C：5烷基與烷二芳基係各自 獨立」^未經取代或經由1至3個各自獨立之選自R13” ：馨 之取長基組成之群取代者，與 : ⑴R14’係由下列之基組成之群：齒基、C1_C8烷基、Ci_C5 ’ 自燒基、CVC5烷氧基與芳基C(rC4烷基，或 (u)其醫藥可接受之鹽。 2·根據申請專利範圍第1項之化合物，其係具結構式πCyclocyclyl-C0_2-alkyl;, (r) R13 and R14 are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, aryl and arylmethyl, and ^ ―Substituted by unsubstituted or independently substituted alkyl groups through groups of 1 to 3 independent substituents selected from R13 ′, and their arylmethyl groups and aryl groups are mutually exclusive Unsubstituted or independent groups consisting of 1 to 3 3 independent groups selected from R14, 1 generation; (s) R13 'is a group consisting of the following groups: C "C5 alkyl , C3_C6 cycloalkyl, CVC5 haloalkyl, (VC5 alkoxy, aryloxy, halo, aryl, _C (0) CVC5 alkyl, _C (0) · aryl, Ci-C5 alkoxy Alkyl, aryl CVC5 alkyl and CrCs alkyl diaryl, and -C (〇) _ aryl, aryl, aryl C ^ C: 5 alkyl and alkyl diaryl are independent " Substituted or substituted by 1 to 3 independently selected from R13 ": Xin's long group, and: ⑴R14 'is a group consisting of the following groups: tooth group, C1_C8 alkyl group, Ci_C5' self-burning , CVC5 alkoxy and aryl C (rC4 alkyl Or (u) of the pharmaceutically acceptable salt thereof. 2. The compound according to item 1 in accordance with the scope of the patent application, which is based structural formula π 〇 II 85504.doc -5- 200406371 之Γ:Γ氫、C1，基、芳基與”基組成 子其中-孩烷基、芳基與芳甲基係各自未經取 1至3個各自獨立之選自R14，之取代基組成之群所=由 .=中請專利範圍第_項之化合物，其係具下列結構〇II 85504.doc -5- 200406371 of Γ: Γ hydrogen, C1, radical, aryl and "group" wherein-alkyl, aryl and arylmethyl are each independently selected from 1 to 3 Group selected from the group consisting of substituents of R14 = compounded by the item _ in the patent scope of. =, Which has the following structure 其中’ R19係選自氳、C1-C4烷基、芳基與芳甲基組成之 群，其中該烷基、芳基與芳甲基係各自未經取代或經由 1至3個各自獨立之選自R14，之取代基所取代。 4·根據申請專利範圍第項之化合物，其中旧係選自氫 、C「C4烷基與芳基（^丄4,烷基組成之群，R2係選自芳基 C〇X4烷雜芳基CqC4烷基組成之群，。 5·根據申請專利範圍第丨或2項之化合物，其中尺2係選自下 列之基組成之群，芳基C()_C4烷基、Ci-C；8烷基、雜芳基 C〇-C4燒基、C3_C6環烷基、Cg C4烷基{⑼—雜^心烷基 、芳基雜匚广^烷基，其中，每一個該化2係未經取代或經 由1至2個各自獨立之選自下列之取代基組成之群取代者 :苯基、鹵苯基、苯氧基、鹵基、鹵基Cl-c4烷基、cvc：4 烷氧基與C3-C6環烷基。 6·根據申請專利範圍第5項之化合物，其中R2為芳基 85504.doc -6- 200406371 烷基，其中该方基為苯基或莕基，而該Cg_C4烷基係選自 甲基、乙章與不存在者，亦即C〇烷基組成之群。 ^ 7·根據申請專利範圍第5項之化合物，其中R2為雜芳基、 c0-C4烷基，而孩雜芳基CqX4烷基為未經取代或經由i至3 · 個各自獨JL之選自R2’之取代基組成之群所取代；而且， 其中該雜芳基係選自下列各物組成之群：吡啶、嘧唑、 苯并違u坐與嘍二吐；而該烷基係選自甲基、乙基與不存 在者，亦即C〇烷基組、成之群。 8·根據申專利範圍第5項之化合物，其中R2為芳基雜士 Ci-Cs燒基’其中該芳基雜Clx8烷基為未經取代或經 至3個各自獨立之選自R2,之取代基組成之群所取代；其 中該芳基為苯基，而該雜原子係選自氮、硫與氧組成之 群。Wherein, R19 is selected from the group consisting of fluorene, C1-C4 alkyl, aryl, and arylmethyl, wherein the alkyl, aryl, and arylmethyl are each unsubstituted or independently selected by 1 to 3 Since R14, the substituent is substituted. 4. The compound according to item 1 of the scope of the patent application, wherein the former is selected from the group consisting of hydrogen, C, C4 alkyl and aryl (^ 4, alkyl, and R2 is selected from the group consisting of aryl Cox4 alkylheteroaryl A group consisting of CqC4 alkyl groups. 5. The compound according to item 丨 or 2 of the scope of the application for patents, wherein Chi 2 is a group selected from the group consisting of aryl C () _ C4 alkyl groups, Ci-C; 8 alkanes. Alkyl, heteroaryl C0-C4 alkyl, C3_C6 cycloalkyl, Cg C4 alkyl {{-heteroalkyl}, arylheteroalkyl}, wherein each of these compounds is unsubstituted Or substituted by a group consisting of 1 to 2 independent substituents selected from: phenyl, halophenyl, phenoxy, halo, halo Cl-c4 alkyl, cvc: 4 alkoxy and C3-C6 cycloalkyl. 6. The compound according to item 5 of the scope of patent application, wherein R2 is aryl 85504.doc-6-200406371 alkyl, wherein the square group is phenyl or fluorenyl, and the Cg_C4 alkyl It is selected from the group consisting of methyl, chapter B, and non-existent, that is, C0 alkyl groups. ^ 7. Compounds according to item 5 of the scope of patent application, wherein R2 is heteroaryl, c0-C4 alkyl, and Heteroaryl CqX4 alkane Is unsubstituted or substituted by a group consisting of i to 3 JJ's substituents selected from R2 '; and wherein the heteroaryl group is selected from the group consisting of pyridine, pyrazole, Benzobenzene and dioxetine; and the alkyl group is selected from the group consisting of methyl, ethyl, and non-existent, that is, the C0 alkyl group. 8. Compounds according to item 5 of the scope of patent application Where R2 is an aryl hetero-Ci-Cs alkyl group, wherein the aryl hetero-Clx8 alkyl group is unsubstituted or substituted by three groups each independently selected from R 2; The group is phenyl, and the heteroatom is selected from the group consisting of nitrogen, sulfur, and oxygen. 9·根據申請專利範圍第1或2項之化合物，其中該R2基係經 由1至2個各自獨立之選自下列之取代基組成之群所取代 :甲基、__乙基、第三-丁基 '氟、氯、嗅、三氟甲基、甲 氧基、乙氧基、苯基與苯氧基。 10·根據申請專利範圍第1或2項之化合物，其中R1與R2—起 形成選自喊啶、喊畊與二氫異喳淋組成之群，其中該旅 啶、哌畊與二氫異喹啉係未經取代或經由1至3個各自獨 立之選自下列之取代基組成之群所取代：烷基、苯 . 基、自苯基、三氟甲基苯基、甲基苯基、甲氧苯基、乙 醯苯基、苄基、鹵芊基、苄醯基、鹵芊醯基、三氟甲基 苄醯基、甲基苄醯基、甲氧苄醯基、乙醯芊醯基、二苯 一 85504.doc 200406371 基亞甲基、（苯基）（由苯基）亞甲基肖二齒苯基亞甲基。 11·根據申請令利範圍第1或2項之化合物，其中竭、未經取 代或獨立經由1至3個各自獨立之選自R2，之基所取代，其 中R1係選自下列之基組成之群：9. The compound according to item 1 or 2 of the scope of patent application, wherein the R2 group is substituted by 1 to 2 groups each independently selected from the following: methyl, __ethyl, third- Butyl'fluoro, chloro, ol, trifluoromethyl, methoxy, ethoxy, phenyl and phenoxy. 10. The compound according to item 1 or 2 of the scope of the patent application, in which R1 and R2 form together a group selected from the group consisting of oxidine, oxamine and dihydroisohydrazone, wherein the acetidine, piperidine and dihydroisoquine The phthaloline is unsubstituted or substituted by 1 to 3 groups each independently selected from the group consisting of alkyl, benzene, phenyl, triphenyl, trifluoromethylphenyl, methylphenyl, methyl Oxyphenyl, ethynyl, benzyl, halofluorenyl, benzylfluorenyl, halofluorenyl, trifluoromethylbenzylfluorenyl, methylbenzylfluorenyl, methoxybenzylfluorenyl, ethenyl , Diphenyl-85504.doc 200406371 methylene, (phenyl) (by phenyl) methylene stilbene phenylmethylene. 11. The compound according to item 1 or 2 of the application, wherein it is substituted, unsubstituted, or independently substituted by 1 to 3 groups independently selected from R2, wherein R1 is selected from the group consisting of group: 12 ·根據申請專利範圍第1或2項之化合物，其中R2為 -ch(c(o)och3)苄基。 13·根據申專利範圍第丨或2項之化合物，其中尺6係選自氫 、Ci-C4虎基與芳基_cG-4-燒基所組成之群，其中該燒基與 务燒基係各自獨立之經由1至3個各自獨立之選自，之 取代基組成之群所取代。 14·根據申請專利範圍第1或2項之化合物，其中义5為η或甲 基。 15·根據申請專利範圍第1或2項之化合物，其中RggCbCg 烷基。 16·根據申請專利範固第！或2項之化合物，其中尺6為甲基。 85504.doc 200406371 17·根據申請專利範圍第1或2項之化合物，其中E為 C(R3)(R4fA。 18·根據申請專利範圍第1或2項之化合物，其中R5為氫或甲 基、烷基，而E為C(R3)(R4)A，且烷 氧基。 19·根據申請專利範圍第1或2項之化合物，其中e為 C(R3)(R4)A，而 A為 C(0)0R26，R6為 烷基。 20·根據申請專利範圍策1或2項之化合物，其係具結構式IV ··12 · The compound according to item 1 or 2 of the scope of application, wherein R2 is -ch (c (o) och3) benzyl. 13. The compound according to item 丨 or 2 of the scope of the patent application, wherein the rule 6 is selected from the group consisting of hydrogen, Ci-C4 tiger group and aryl_cG-4-alkyl group, wherein the alkyl group and alkyl group Each is independently replaced by a group consisting of 1 to 3 independent substituents selected from. 14. A compound according to item 1 or 2 of the scope of patent application, wherein meaning 5 is η or methyl. 15. A compound according to item 1 or 2 of the scope of application, wherein RggCbCg is alkyl. 16. According to the patent application Fan Gudi! Or a compound of 2 wherein 6 is methyl. 85504.doc 200406371 17. Compound according to item 1 or 2 of the scope of patent application, where E is C (R3) (R4fA. 18. Compound according to item 1 or 2 of the scope of patent application, wherein R5 is hydrogen or methyl, Alkyl, and E is C (R3) (R4) A, and alkoxy. 19. Compounds according to item 1 or 2 of the scope of patent application, where e is C (R3) (R4) A, and A is C (0) 0R26 and R6 are alkyl groups. 20. Compounds according to item 1 or 2 of the scope of the patent application, which have the structural formula IV ... 其中，R11係選自芳基、-C(O)芳基、鹵基烷氧基、 Q-C5烷芳基、烷二芳基、芳氧基、與C1-C6烷基所 組成之群，其中該芳基、-C(O)芳基、鹵基烷氧基 C1 - C 5^¾方基、C1 - C 5 方基與C1 - C 6燒基係各自獨立 之未經取代或各自獨立之經由1至3個各自獨立之選自 R1’之取代基組成之群所取代。 21 ·根據申請專利範圍第1或2項之化合物，其係具結構式v :Among them, R11 is selected from the group consisting of aryl, -C (O) aryl, haloalkoxy, Q-C5 alkaryl, alkdiaryl, aryloxy, and C1-C6 alkyl, The aryl group, -C (O) aryl group, haloalkoxy group C1-C 5 ^ ¾, C1-C 5 and C1-C 6 are independently unsubstituted or independently. It is replaced by a group consisting of 1 to 3 independent substituents selected from R1 ′. 21 · The compound according to item 1 or 2 of the scope of patent application, which has the structural formula v: 其中，R12係選自芳基、芳氧基、芳基、鹵基(^Χ5 85504.doc Λ 200406371 埝氧基、CbCs烷芳基、Ci-Cs烷二芳基與C1-C6烷基所組 成之群，术中該芳基、-C(O)芳基、鹵基Cl_C5烷氧基、二 C1-C5烷芳基、Ci-Cs烷二芳基與C1-C6烷基係各自獨立之 、 未經取代或各自獨立之經由1至3個各自獨立之選自ri，-之取代基組成之群所取代。 22 ·根據申請專利範圍第1或2項之化合物，其係具結構式vi :Among them, R12 is selected from the group consisting of aryl, aryloxy, aryl, halo (^ × 5 85504.doc Λ 200406371 alkoxy, CbCs alkylaryl, Ci-Cs alkyldiaryl, and C1-C6 alkyl In the group, the aryl group, -C (O) aryl group, halo Cl_C5 alkoxy group, di C1-C5 alkaryl group, Ci-Cs alkane diaryl group, and C1-C6 alkyl group are each independently, Unsubstituted or independently substituted by 1 to 3 independent groups consisting of substituents selected from ri,-. 22 · The compound according to item 1 or 2 of the scope of patent application, which has the structural formula vi: 其中，R12係選自芳基、芳氧基、_c(〇)芳基、鹵基CiX5 &amp;氧基、CkC5燒芳基、Cl_C5烷二芳基與C1-C6^基所組 成之群，其中該芳基、_C(〇)芳基、鹵基烷氧基、 c^c：5烷芳基、ClX5烷二芳基與c1-C6烷基係各自獨立之 未經取彳1或各自獨立之經由1至3個各自獨立之選自R1， &lt;取代基組成之群所取代；R25係選自C1-C4烷基、鹵基— 、鹵基C1_C3烷基、ci_C5烷氧基與苯基組成之群。 ， 3·根據申明專利乾園第丨或]項之化合物，其係具結構式:Among them, R12 is selected from the group consisting of aryl, aryloxy, _c (〇) aryl, halo CiX5 &amp; oxy, CkC5 aryl, Cl_C5 alkyldiaryl and C1-C6 ^ group, where The aryl group, _C (〇) aryl group, haloalkoxy group, c ^ c: 5 alkylaryl group, ClX5 alkyldiaryl group, and c1-C6 alkyl group are each independently Substituted by 1 to 3 groups independently selected from R1, &lt;substituents; R25 is selected from C1-C4 alkyl, halo-, halo C1-C3 alkyl, ci_C5 alkoxy and phenyl Group. 3. According to the declared patent dry item 丨 or], the compound has the structural formula: /R12 85504.doc VII 200406371 其中，R12係選自芳基、芳氧基、-C(0)芳基、鹵基 烷氧基、芳基CVC5烷基、CbQ烷二芳基與C1-C6烷基所 Ί 組成之群，其中該芳基、-C(O)芳基、芳氧基、鹵基 烷氧基、烷芳基、CbCs烷二芳基與C1-C6烷基係各 ’ 自獨立之未經取代或各自獨立之經由1至3個各自獨立之 選自R1’之取代基組成之群所取代；R25係選自C1-C4烷 基、鹵基、卣基C1-C3烷基、C1-C5烷氧基與苯基組成之/ R12 85504.doc VII 200406371 where R12 is selected from the group consisting of aryl, aryloxy, -C (0) aryl, haloalkoxy, aryl CVC5 alkyl, CbQ alkyldiaryl, and C1-C6 alkyl A group consisting of aryl groups, wherein the aryl group, -C (O) aryl group, aryloxy group, haloalkoxy group, alkaryl group, CbCs alkanediaryl group and C1-C6 alkyl group are each independently independent Unsubstituted or independently substituted by 1 to 3 groups each independently selected from R1 ′; R25 is selected from C1-C4 alkyl, halo, fluorenyl C1-C3 alkyl, C1-C5 alkoxy and phenyl 24·根據申讀::專利範圍第1項之化合物，其係選自下列各物組 9 成之群；' (2S，l’R)-2_乙氧基-3-(4-{1，·[2-(4_苯氧基-苯基）-乙基胺 甲醯基]_乙氧基}-苯基）-丙酸，（2S，l’R)-2-乙氧基-3-(4-{l’-[2-(4-乙基-苯基）-乙基胺甲醯基]-乙氧基}-苯基）_ 丙酸，（2S，l’R)_2_乙氧基·3-(4-{1’-[2-(4•三氟甲基苯 基）-乙基胺甲醯基]-乙氧基}•苯基）-丙酸； (2S，l’Rl-2-乙氧基_3·(4-{1，-[2-(2-乙氧基·苯基）-乙基胺 甲酿基]&quot;乙氧基苯基）-丙酸； (2S，l，R)-2-乙氧基-3-{4_[1，·(3-三氟甲基苄基胺甲醯基） -乙氧基]-苯基}•丙酸； (2S，1，R&gt;2-乙氧基-3-{4-[1，-(3-氟基-5·三氟甲基-苄基胺 、 甲醯基）-乙氧基]-苯基}-丙酸； . (2S, 1 R)~3-(4-{l -[(一丰基-3-基甲基）-胺甲酿基]-乙氧 基}-苯基）-2-乙氧基·丙酸； (2S，l’R)-3-(4-{l’-[2-(3-氯基-苯基）-乙基胺甲醯基]-乙 一 85504.doc -11 - 200406371 氧基}-苯基）-2-乙氧基·丙酸； (2S，l’R)，2•乙氧基-3-(4{1，·[2-(3-氟基·苯基）-乙基胺甲 1 醯基]-乙氧基}-苯基）·丙酸； (2S，l’R)-2-乙氧基_3-(4{1，-〇(2-氟基-苯基）_乙基胺甲 、 酸基]-乙氧基卜苯基）-丙酸； (2S, l’R)-3-(4{l’-[2_(2,4_二氯基-苯基）_ 乙基胺甲醯基]-乙氧基}-苯基）-2-乙氧基-丙酸； (2S，l’R)-3-(4{l’_[2&gt;(2,6-二氯基-苯基）-乙基胺甲醯基]· 乙氧苯基）-2-乙氧基-丙酸； 9 (2S，l’R)-3:(4{r_[2_(2-氯基-苯基）-乙基胺甲醯基]•乙氧 基}-苯基）-2-乙氧基-丙酸，（2S，l’R)-3-(4{l’_[2_(4-弟 三-丁基&quot;苯基）-乙基胺甲醯基]-乙氧基}-苯基）-2 -乙氧 基-丙酸，；24 · According to the application: The compound in the first scope of the patent is selected from the group consisting of 90% of each of the following groups; '(2S, l'R) -2_ethoxy-3- (4- {1 , · [2- (4-phenoxy-phenyl) -ethylaminemethyl] -ethoxy} -phenyl) -propionic acid, (2S, l'R) -2-ethoxy- 3- (4- {l '-[2- (4-ethyl-phenyl) -ethylaminomethylmethyl] -ethoxy} -phenyl) _propionic acid, (2S, l'R) _2 _Ethoxy · 3- (4- {1 '-[2- (4 • trifluoromethylphenyl) -ethylaminomethyl} -ethoxy} • phenyl) -propionic acid; (2S , L'Rl-2-ethoxy_3 · (4- {1,-[2- (2-ethoxy · phenyl) -ethylaminomethyl]] &quot; ethoxyphenyl)- Propionic acid; (2S, l, R) -2-ethoxy-3- {4_ [1, · (3-trifluoromethylbenzylaminemethylamidino) -ethoxy] -phenyl} • propane Acid; (2S, 1, R &gt; 2-ethoxy-3- {4- [1,-(3-fluoroyl-5 · trifluoromethyl-benzylamine, formamyl) -ethoxy] -Phenyl} -propionic acid;. (2S, 1 R) ~ 3- (4- {l-[(monopentyl-3-ylmethyl) -aminomethyl] -ethoxy} -phenyl ) -2-ethoxy · propionic acid; (2S, l'R) -3- (4- {l '-[2- (3-chloro-phenyl) -ethylaminomethylmethyl] -ethane 85504.doc -11-200 406371 oxy} -phenyl) -2-ethoxy · propionic acid; (2S, l'R), 2 • ethoxy-3- (4 {1, · [2- (3-fluoroyl · benzene Group) -ethylaminomethyl 1 fluorenyl] -ethoxy} -phenyl) · propionic acid; (2S, l'R) -2-ethoxy_3- (4 {1, -〇 (2- Fluoro-phenyl) -ethylaminomethyl, acid] -ethoxybuphenyl) -propionic acid; (2S, l'R) -3- (4 {l '-[2_ (2,4_ Dichloro-phenyl) _ethylaminomethyl} -ethoxy} -phenyl) -2-ethoxy-propionic acid; (2S, l'R) -3- (4 {l'_ [2 &gt; (2,6-dichloro-phenyl) -ethylaminomethyl]] ethoxyphenyl) -2-ethoxy-propionic acid; 9 (2S, l'R) -3: (4 {r_ [2_ (2-chloro-phenyl) -ethylaminomethylmethyl] • ethoxy} -phenyl) -2-ethoxy-propionic acid, (2S, l'R)- 3- (4 {l '_ [2_ (4-Ditri-butyl &quot; phenyl) -ethylaminomethylmethyl] -ethoxy} -phenyl) -2 -ethoxy-propionic acid, ; (2S，l’R)-2-乙氧基_3·{4_[1’_(4-氟基·苄基胺甲醯基）-乙 氧基]-苯基卜丙酸，（2S，l，R)-2-乙氧基-3_{4-[Γ-(4_三 氟甲查_-苄基胺甲醯基）-乙氧基]-苯基卜丙酸； (2S，l’Rf-3_{4-[l’_(4-第三-丁基-芊基胺甲醯基）-乙氧基] -苯基}-2-乙氧基-丙酸，（2S，l，R)-3_{4-[l，-(4_第三-丁 基-苯基胺甲醯基）-乙氧基]-苯基}-2-乙氧基-丙酸， (2S，l’R)-3-{4-[l’-(4-反式-第三-丁基-環己基胺甲醯 基）-乙氧基]-苯基}-2-乙氧基-丙酸； (2 S)-3-{4-[1-(4•第三-丁基-環己基胺甲醯基）-1-甲基-乙 氧基]-苯基卜2-甲氧基-丙酸； (2S)-2-甲氧基_3_(4·{1-甲基-l-[2_(4-苯氧基-苯基）_乙基 85504.doc -12- 胺甲醯基）-乙氧基]-苯基}-丙酸； (2S)-3-(4-1-l-[2-(2-乙氧基-苯基）_乙基胺甲醯基]-1-甲基_ : 乙氧基}-苯基）-2-甲氧基-丙酸； 、 2-甲氧基-3-(4-{l-甲基-l-[2-(3-三氟甲基-苯基）-乙基胺 、 甲醯基]-乙氧基卜苯基）-丙酸； (2S)-2-甲氧基-3-{4-[l-甲基-1-(3-三氟甲基-芊基胺甲醯 基）_乙氧基]•苯基}-丙酸，（2S)_3_(4-{l-[2-(2-氯基-苯 基）-乙基胺甲醯基1-1-甲基-乙氧基卜笨基）-2-甲氧基- 丙酸；； 二 —» 、 (2S)-3-(_4-{I-[(二苯基-3-基甲基）-胺甲醯基]-卜甲基·乙 氧基}-苯基）-2-甲氧基-丙酸； (2S)-3-(4-{l-[2-(2,5-二甲氧基-苯基）_乙基胺甲醯基]-1-甲基-乙氧基}-苯基）-2-甲氧基-丙酸； (23)-3-(4_{1-[2-(2-氟基-苯基）-乙基胺甲醯基]-卜甲基-乙 氧基卜苯基）-2-甲氧基-丙酸；(2S, l'R) -2-ethoxy-3 · {4_ [1 '_ (4-fluoro · benzylaminemethylamidino) -ethoxy] -phenylpropanoic acid, (2S, l, R) -2-ethoxy-3_ {4- [Γ- (4-trifluoromethane_-benzylamine formamyl) -ethoxy] -phenylpropanoic acid; (2S, l 'Rf-3_ {4- [l' _ (4-Third-butyl-fluorenylaminomethylmethyl) -ethoxy] -phenyl} -2-ethoxy-propionic acid, (2S, l , R) -3_ {4- [l,-(4-Third-butyl-phenylaminomethylmethyl) -ethoxy] -phenyl} -2-ethoxy-propionic acid, (2S, l'R) -3- {4- [l '-(4-trans-third-butyl-cyclohexylaminemethylamidino) -ethoxy] -phenyl} -2-ethoxy-propyl Acid; (2 S) -3- {4- [1- (4 • Third-butyl-cyclohexylaminemethylamidino) -1-methyl-ethoxy] -phenylbutan-2-methoxy -Propionic acid; (2S) -2-methoxy_3_ (4 · {1-methyl-l- [2_ (4-phenoxy-phenyl) _ethyl 85504.doc -12-amine formamidine ) -Ethoxy] -phenyl} -propionic acid; (2S) -3- (4-1-l- [2- (2-ethoxy-phenyl) _ethylaminemethyl]- 1-methyl-: ethoxy} -phenyl) -2-methoxy-propionic acid; 2-methoxy-3- (4- {l-methyl-l- [2- (3- Trifluoromethyl-phenyl) -ethylamine, methylamidino] -ethoxyphenyl ) -Propionic acid; (2S) -2-methoxy-3- {4- [l-methyl-1- (3-trifluoromethyl-fluorenylaminomethylmethyl) _ethoxy] • benzene } -Propanoic acid, (2S) _3_ (4- {l- [2- (2-chloro-phenyl) -ethylaminomethylmethyl-1--1-methyl-ethoxybenzyl)- 2-methoxy-propionic acid; di- », (2S) -3-(_ 4- {I-[(diphenyl-3-ylmethyl) -aminomethylmethyl] -methylmethylethoxy } -Phenyl) -2-methoxy-propionic acid; (2S) -3- (4- {l- [2- (2,5-dimethoxy-phenyl) -ethylaminomethylamino ] -1-methyl-ethoxy} -phenyl) -2-methoxy-propionic acid; (23) -3- (4_ {1- [2- (2-fluoroyl-phenyl) -ethyl Methylaminomethylmethyl] -methyl-ethoxybenzoyl) -2-methoxy-propionic acid; (2S)-2-乙氧基-3-(4-{l-甲基-1-[2·(3_三氟甲基-苯基）-乙 基胺甲~酸基]-乙氧基卜笨基）-丙酸； (2S)_2-乙氧基-3-{4-[1-(3-氟基-5-三氟甲基-芊基胺甲醯 基）-1-甲基-乙氧基]-苯基}-丙酸； (2S)-3-(4-{l-[2-(2-氯基-苯基）-乙基胺甲醯基]-1·甲基-乙 氧基卜苯基）-2·乙氧基-丙酸，（2S)-3-(4-{l-[(二苯基-3-基甲基）-胺甲醯基l·1-甲基-乙氧基卜苯基）-2·乙氧基- 丙酸； (2S)-3-(4-{l-[2-(3-氯基-苯基）-乙基胺甲醯基]-1-甲基-乙一 85504.doc -13- 200406371 氧基卜苯基）-2-乙氧基-丙酸； (2S)-3-(4-11-[2-(2,5-二甲氧基-苯基）-乙基胺甲醯基]-1-甲基-乙氧基}-苯基）-2 -乙氧基-丙酸； (2S)-2-乙氧基_3-(4_{1-[2_(2 -氟基-苯基）-乙基胺甲酿基] -1-甲基-乙氧基}-苯基）-丙酸； (2S)-3-{3_[l-(4·第二-丁基-環己基胺甲酸基）-1-甲基-乙 氧基]-苯基}-2-甲氧基-丙酸； (2S)-3-{3-[l-(3 -氟基-5-三氟甲基-爷基胺甲酸基）-1·甲基 -乙氧基—]·苯基}-2-甲氧基-丙酸； .〜 (2S)-3-(3-{f-[(二苯基·3-基甲基）-胺甲驢基]-1-甲基-乙 氧基}-苯基）-2 -甲氧基-丙酸； (2S)-3-(3-{l-[2-(3-氯基-苯基）-乙基胺甲醯基]-1-甲基-乙 氧基}-苯基）-2 -甲氧基-丙酸； (2S)-2_甲氧基-3-{4-[(l-苯基-乙基胺甲醯基）-甲氧基]-苯 基}-丙酸； (2S)-3-(3_{l-[2-(2,4 -二氯基-苯基）-乙基胺甲酸基]-1-甲 基-乙氧基}-苯基）-2 -甲氧基-丙酸； (2S)-3-(3-{l-[2-(2,6 -二氯基-苯基）-乙基胺甲酿墓]·1-甲 基-乙氧基}-苯基）-2-甲氧基-丙酸； (23)-3-(4-{1-[2-(2,4-二氣基-苯基）-乙基胺甲醯基]-1-甲 基-乙氧基卜苯基）-2_甲氧基-丙酸； (2S)-3_(4-{l-[2-(2,4 -二氯基-苯基）-乙基胺甲酸基]_1-甲 基-乙氧^基}-琴基）-2 -乙乳基-丙酸； (2S)_3-(4-{l-[2-(2,6-二氯基-苯基）-乙基胺甲酿基]-1-甲 85504.doc -14- 200406371 基-乙氧基}-苯基）-2·乙氧基-丙酸； (28)-2-乙|基-3-(4_{1-[2-(4-乙基-苯基）_乙基胺甲醯基]^ -1-甲基-乙氧基卜苯基）-丙酸； ’ (2S)-2-乙氧基-3-(4-{1-[2-(2·乙氧基-苯基）_乙基胺甲醯· 基]甲基-乙氧基}•苯基）·丙酸； 2·乙氧基-3-{4-[ 1-(3-三氟甲基-苄基胺甲醯基）_乙氧基]_ 苯基}-丙酸； 2·乙氧基-3-{4-[ 1-(5-'氟基-3-三氟甲基-芊基胺甲醯基 乙氧基+苯基}-丙酸； 3 2- 乙氧基·3:{4-[1-(3-苯基-芊基胺甲醯基乙氧基]-苯基} -丙酸； 2_乙乳基-3-{4-[1-(4-苯氧基-苯基乙基胺甲酸基)-乙氧基] -苯基卜丙酸； 2_乙氧基-3-{4-[l-(3-三氟甲基-苯基乙基胺〒酸基）-乙氧 基]-苯基}-丙酸； 3- (4_{1_[2-(2,6 -二氯基-苯基）-乙基胺甲酿基]-乙乳基}- ： 苯基）-2-乙氧基-丙酸； 〜 2-乙氧基-3-(4-{1_[2-(4·乙基-苯基）·乙基胺甲醯基]-乙氧 &gt; 基}-苯基）-丙酸； 2- 乙氧基-3-(4-{1·[2-(4-乙基-苯基）-乙基胺甲醯基]-乙氧 、 基卜苯基）-丙酸； 植 3- (4-{環己基_[2-(4-乙基-苯基）-乙基胺甲醯基]-甲氧基}-苯基）-2-乙氧基-丙酸； 2-乙氧基_3_(4_{l-[2-(4-乙基-苯基）-乙基胺甲醯基]-2-苯 - 85504.doc -15- 200406371 « 基-乙氧基}-苯基）-丙酸，與 -乙氧基]-苯基}-丙酸；及 Γ 其醫藥可接受之鹽。 麵 25.根據申請專利範圍第1項之化合物，其中該化合物係選自 下列各物組成之群： (2S’ l，R)-3-{4-[l-(4-第三-丁基·環己基胺甲酷基）_乙氧基] -苯基}_2_乙氧基-為酸；(2S) -2-ethoxy-3- (4- {l-methyl-1- [2 · (3-trifluoromethyl-phenyl) -ethylaminomethyl ~ acidyl] -ethoxy Bubenyl) -propionic acid; (2S) _2-ethoxy-3- {4- [1- (3-fluoroyl-5-trifluoromethyl-fluorenylaminomethylmethyl) -1-methyl -Ethoxy] -phenyl} -propionic acid; (2S) -3- (4- {l- [2- (2-chloro-phenyl) -ethylaminomethylmethyl] -1 · methyl -Ethoxybuphenyl) -2 · ethoxy-propionic acid, (2S) -3- (4- {l-[(diphenyl-3-ylmethyl) -aminomethylamidino 1.1 -Methyl-ethoxyphenyl) -2 · ethoxy-propionic acid; (2S) -3- (4- {l- [2- (3-chloro-phenyl) -ethylamine methyl Fluorenyl] -1-methyl-ethane-85504.doc -13- 200406371 oxyphenylphenyl) -2-ethoxy-propionic acid; (2S) -3- (4-11- [2- (2, 5-dimethoxy-phenyl) -ethylaminomethylmethyl] -1-methyl-ethoxy} -phenyl) -2-ethoxy-propionic acid; (2S) -2-ethoxy -3- (4_ {1- [2_ (2-fluoro-phenyl) -ethylaminomethyl] -1-methyl-ethoxy} -phenyl) -propionic acid; (2S)- 3- {3_ [l- (4 · Second-butyl-cyclohexylaminocarboxylic acid) -1-methyl-ethoxy] -phenyl} -2-methoxy-propionic acid; (2S)- 3- {3- [l- (3-Fluoro-5-trifluoromethyl-methylaminocarbamate) -1 · Methyl-ethoxy—] · phenyl} -2-methoxy-propionic acid;. ~ (2S) -3- (3- {f-[(diphenyl · 3-ylmethyl) -amine Medonyl] -1-methyl-ethoxy} -phenyl) -2-methoxy-propionic acid; (2S) -3- (3- {l- [2- (3-chloro-benzene Group) -ethylaminomethylmethyl] -1-methyl-ethoxy} -phenyl) -2-methoxy-propionic acid; (2S) -2_methoxy-3- {4- [ (l-phenyl-ethylaminomethyl) -methoxy] -phenyl} -propionic acid; (2S) -3- (3_ {l- [2- (2,4-dichloro-benzene ) -Ethylaminoformyl] -1-methyl-ethoxy} -phenyl) -2-methoxy-propionic acid; (2S) -3- (3- {l- [2- (2 , 6 -dichloro-phenyl) -ethylamine methylbenzene] · 1-methyl-ethoxy} -phenyl) -2-methoxy-propionic acid; (23) -3- (4 -{1- [2- (2,4-dioxo-phenyl) -ethylaminomethylmethyl] -1-methyl-ethoxybphenyl) -2-methoxy-propionic acid; (2S) -3_ (4- {l- [2- (2,4-dichloro-phenyl) -ethylcarbamate] _1-methyl-ethoxy ^ -yl} -2- Ethyl lactyl-propionic acid; (2S) _3- (4- {l- [2- (2,6-dichloro-phenyl) -ethylaminomethyl]]-1-methyl 85504.doc -14 -200406371 yl-ethoxy} -phenyl) -2 · ethoxy-propionic acid; (28) -2-ethyl | yl-3- (4_ {1- [2- (4-ethyl-phenyl) -ethylaminomethylmethyl] ^-1-methyl-ethoxyphenylphenyl) -propionic acid; '(2S) -2-ethoxy-3 -(4- {1- [2- (2 · ethoxy-phenyl) _ethylamine formamidine · methyl] methyl-ethoxy} • phenyl) · propionic acid; 2 · ethoxy- 3- {4- [1- (3-trifluoromethyl-benzylamine formamyl) _ethoxy] _phenyl} -propionic acid; 2. · ethoxy-3- {4- [1- (5-'Fluoro-3-trifluoromethyl-fluorenylaminomethylmethylethoxy + phenyl} -propionic acid; 3 2-ethoxy · 3: {4- [1- (3-benzene -Methylaminomethylmethylethoxy] -phenyl} -propionic acid; 2-ethylethoxy-3- {4- [1- (4-phenoxy-phenylethylaminocarboxylic acid)- Ethoxy] -phenylpropanoic acid; 2-ethoxy-3- {4- [l- (3-trifluoromethyl-phenylethylaminesulfonyl) -ethoxy] -phenyl } -Propionic acid; 3- (4_ {1_ [2- (2,6-dichloro-phenyl) -ethylaminomethyl] -ethoxylate}-: phenyl) -2-ethoxy -Propionic acid; ~ 2-ethoxy-3- (4- {1_ [2- (4 · ethyl-phenyl) · ethylaminomethylmethyl] -ethoxy &gt; yl} -phenyl)- Propionic acid; 2-ethoxy-3- (4- {1 · [2- (4-ethyl-phenyl) -ethylaminomethylmethyl] -ethoxy, phenylphenyl) -propionic acid; Plant 3- (4- {ring Hexyl_ [2- (4-ethyl-phenyl) -ethylaminomethylmethyl] -methoxy} -phenyl) -2-ethoxy-propionic acid; 2-ethoxy_3_ (4_ {l- [2- (4-ethyl-phenyl) -ethylaminomethylmethyl] -2-benzene- 85504.doc -15- 200406371 «yl-ethoxy} -phenyl) -propionic acid, And -ethoxy] -phenyl} -propionic acid; and Γ its pharmaceutically acceptable salts. 25. The compound according to item 1 of the scope of patent application, wherein the compound is selected from the group consisting of: (2S 'l, R) -3- {4- [l- (4-third-butyl · Cyclohexylaminomethyl) -ethoxy] -phenyl} _2_ethoxy- is an acid; (2S，rRp乙氧基·3_(4·{1’-[(嘆吩_2•基甲基）_胺甲酿基] -乙氧·基厂·苯基）-丙酸； (2S，l，R)-2-乙氧基分_2·基乙基胺甲醯基) -乙氧基]-苯基卜丙酸；及 其醫藥可接受之鹽。 26.根據申請專利範圍第丨項之化合物，其中該化合物為(2S, rRp ethoxy · 3_ (4 · {1 '-[(thiophen_2 • ylmethyl) _aminomethyl] -ethoxy · base plant · phenyl) -propionic acid; (2S, l, R) -2-ethoxy-2-ylethylaminomethyl) -ethoxy] -phenylpropanoic acid; and pharmaceutically acceptable salts thereof. 26. The compound according to item 丨 of the application, wherein the compound is J OH OEt ;或其醫藥可接受之鹽。 27. 根據申請專利範圍第⑷項之化合物，其係半嗓啡鹽。 28. -種醫藥組合物’包括醫藥可接受載體與至少一種根據 申請專利範園第_項之化合物或其醫藥可接受之鹽。 29. -種調節過氧化物酶體增殖劑活化受體之活體外方法 ’包括步驟為在活體外令該受體與至少_種根據申請專 利範圍第1或2項之化合物或其醫藥可接受之鹽進行接觸。 85504.doc -16- 30 200406371 _ V、 .種治療哺乳類糖尿病之醫藥組合物，包括治療 :至少-衰根據申請專利範固第以2項之化合物或其：— 表可接受之鹽。 31. 32. 33. 34. 35. 36. 一種預防哺乳類糖尿病之醫藥組合物，包括有效量之至· 少—種根據申請專利範圍第丨或2項之化合物或Α — 接受之鹽。 -J OH OEt; or a pharmaceutically acceptable salt thereof. 27. The compound according to item ⑷ of the scope of patent application is a hemi-pharyngeal salt. 28. A pharmaceutical composition 'comprising a pharmaceutically acceptable carrier and at least one compound according to item _ of the patent application park or a pharmaceutically acceptable salt thereof. 29. An in vitro method of regulating a peroxisome proliferator-activated receptor 'includes the step of exposing the receptor in vitro to at least one compound according to item 1 or 2 of the scope of patent application or a pharmaceutically acceptable Contact with salt. 85504.doc -16- 30 200406371 _ V. A pharmaceutical composition for the treatment of mammalian diabetes, including the treatment of at least one compound according to item 2 of the patent application or its:-table acceptable salts. 31. 32. 33. 34. 35. 36. A pharmaceutical composition for the prevention of mammalian diabetes, comprising an effective amount of at least-at least one of the compounds according to the scope of the patent application, or A-accepted salts. - 一種治療哺乳類X症候群之醫藥組合物，包括治療有效 Τ之至少一種根據申請專利範圍第1或2項之化合物，或 其醫藥可接受之鹽。 種如申請〜專利範圍第1或2項所定義之化合物或其醫藥 可接受之鹽之用途，其係用於製造治療糖尿病之醫藥。 根據申請專利範圍第1或2項之化合物或其醫藥可接受之 鹽，其係作為藥物。 一種如申請專利範圍第1或2項所定義之化合物或其醫藥 可接受之鹽之用途，其係用於製造治療或預防哺乳類糖 尿病之醫藥。 一種如青專利範圍第1或2項所定義之化合物或其醫藥 j I 可接受之鹽之用，其係用於製造治療哺乳類X症候群之二 醫藥。- ·〜 85504.doc 17- 200406371 柒、指定代表圖： (一) 本案指定我表圖為：第（ ）圖。 (二) 本代表圖之元件代表符號簡單說明·· 捌、本案若有彳J：學式時，請揭示最能顯示發明特徵的化學式： 、 〇 R5、尸6 /A pharmaceutical composition for treating mammalian X syndrome, comprising at least one compound according to item 1 or 2 of the scope of patent application of a therapeutically effective T, or a pharmaceutically acceptable salt thereof. The use of a compound or a pharmaceutically acceptable salt thereof as defined in item 1 or 2 of the application ~ patent scope is for the manufacture of a medicine for treating diabetes. The compound according to item 1 or 2 of the patent application scope or a pharmaceutically acceptable salt thereof is used as a medicine. A use of a compound or a pharmaceutically acceptable salt thereof as defined in item 1 or 2 of the scope of patent application, which is used for the manufacture of a medicine for treating or preventing mammalian diabetes. A compound as defined in item 1 or 2 of the Qing patent scope or an acceptable salt thereof for pharmaceutical use. It is used for the manufacture of the second medicine for treating mammalian X syndrome. -· ~ 85504.doc 17- 200406371 柒. Designated representative map: (1) The designation of the chart in this case is: (). (II) Brief description of the element representative symbols in this representative diagram ... 捌, if there is 彳 in this case J: When you learn the formula, please reveal the chemical formula that can best show the characteristics of the invention: 、 〇 R5 、 corpse 6 / 〇 R1 R2 85504.doc〇 R1 R2 85504.doc
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